Immunity

Review

Cancer-Cell-Intrinsic Mechanisms
Shaping the Tumor Immune Landscape
Max D. Wellenstein1 and Karin E. de Visser1,*
1Division of Tumor Biology & Immunology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands

*Correspondence: k.d.visser@nki.nl
https://doi.org/10.1016/j.immuni.2018.03.004

Owing to their tremendous diversity and plasticity, immune cells exert multifaceted functions in tumor-
bearing hosts, ranging from anti-tumor to pro-tumor activities. Tumor immune landscapes differ greatly be-
tween and within cancer types. Emerging evidence suggests that genetic aberrations in cancer cells dictate
the immune contexture of tumors. Here, we review the current understanding of the mechanisms whereby
common drivers of tumorigenesis modulate the tumor immune milieu. We discuss these findings in the
context of clinical observations and examine how cancer-cell-intrinsic properties can be exploited to maxi-
mize the benefit of immunomodulatory therapies. Understanding the relationship between cancer cell-
intrinsic genetic events and the immune response may enable personalized immune intervention strategies
for cancer patients.

Introduction cancer cell-extrinsic regulators of cancer biology, the immune

The recognition of cancer as a genetic disease is more than a
century old and stems from observations by David von Hanse-
mann and Theodor Boveri that cancer cells display chromo-
somal abnormalities (Boveri, 1914; von Hansemann, 1890). In
the early 20th century, Francis Rous revealed that retroviruses
could drive sarcoma formation in chickens (Rous, 1911). Many
decades later, in 1970, the Rous sarcoma virus was found to
carry a gene called v-Src, the first oncogene to be identified
(Duesberg and Vogt, 1970; Stehelin et al., 1976). Concurrently,
it was discovered that not only activation, but also inactivation
of so-called tumor suppressor genes (TSGs) can lead to tumor-
igenesis (Knudson, 1971). (Proto-)oncogenes and TSGs regulate
essential cellular processes like cell cycle, apoptosis, migration,
and survival, and genetic aberrations that lead to dysregulation
or loss of function of these genes can result in malignant trans-
formation. The generation of transgenic mice carrying an acti-
vated oncogene, also called oncomice, in the 1980s and TSG
knockout mice in the 1990s further substantiated the notion
that oncogene expression or loss of TSGs in normal mammalian
cells leads to cancer development (Adams et al., 1985; Done-
hower et al., 1992; Hanahan et al., 2007; Stewart et al., 1984).
The dependency of cancers on these dysregulated genes
was demonstrated in genetically engineered mouse models
(GEMMs) in which de-activation of oncogenes or re-expression
of TSGs in fully established tumors led to rapid tumor regression
(Fisher et al., 2001; Jain et al., 2002; Moody et al., 2002; Ventura
et al., 2007). These insights into the causal role of genetic aber-
rations in cancer initiation and progression spurred the long-held
belief that tumorigenesis is entirely driven by cancer-cell-intrinsic
genetic traits. However, over the past couple of decades, this
dogma has been challenged by new experimental evidence
demonstrating that genetic aberrations alone are required, but
not sufficient, for a cancer to develop. Like a seed needing fertile
soil for successful germination, cancer cells only survive and
develop into invasive tumors in an environment that provides
sufficient nutrients and oxygen, and that lacks strong cytotoxic
signals. In this review, we will focus on one of the most influential
system.
Similar to its physiological function, the immune system exerts
multifaceted tasks in tumor-bearing hosts, with different immune
cells playing different and sometimes opposing roles. The
composition and function of immune cells in tumors differs
greatly between, but also within, cancer types. For example, of
the breast cancer subtypes, triple-negative breast cancer
(TNBC) presents with highest levels of tumor-infiltrating lympho-
cytes (TIL) and macrophages (Medrek et al., 2012; Stanton et al.,
2016). Striking differences in relative leukocyte composition be-
tween different tumor types were observed in a study that inte-
grated gene expression and clinical outcome data of over
18,000 human tumors (Gentles et al., 2015). Moreover, this study
revealed considerable variation in intratumoral presence of
certain immune cell subsets and how these were associated
with cancer-specific outcomes. For example, whereas memory
CD4+ T cells were associated with adverse outcome in bladder
cancer patients, they correlated with favorable outcome in lung
adenocarcinoma patients (Gentles et al., 2015), suggesting
that differences in immune profile are not only phenotypically
distinct but are also of functional consequence. But what deter-
mines this substantial variation in immune contexture between
different tumors? Given the surge of interest in utilizing immuno-
modulatory drugs for the treatment of cancer patients, it is crit-
ical to understand the underlying tumor characteristics that
dictate the inter-tumor heterogeneity in immune landscapes
and to use this knowledge for rational decision-making in the
clinical use of immunomodulatory strategies.
In this review, we will discuss recent insights into how cancer
cell-intrinsic properties can dictate the immune landscape of tu-
mor-bearing hosts. Specifically, we will examine which genetic
aberrations correlate with immune cell composition in human
tumors. Next, we will discuss the current knowledge on onco-
gene- and TSG-dependent signaling pathways that underlie
the differential crosstalk of cancer cells with the immune system
as identified in genetically engineered mouse tumor models
(GEMMs). Finally, we will discuss how the growing insights into

Immunity 48, March 20, 2018 ª 2018 Elsevier Inc. 399


these mechanisms may open new avenues for personalized im-
mune intervention strategies for cancer patients.
Genetic Makeup Influencing the Immune Contexture of
Tumors—Observations from the Clinic
In 1863, the German pathologist Rudolf Virchow was the first to
hypothesize a link between the development of tumors and the
inflammatory state of their anatomical location (Balkwill and
Mantovani, 2001). Around the same time, William Coley, pioneer
of cancer immunotherapy, demonstrated that some patients
displayed tumor regression after being injected with immune
stimulatory Streptococcus pyogenes cultures (Coley, 1893).
Nowadays, it is fully established that inflammation can be caus-
ally linked with human cancers and that the immune infiltrate of
human tumors contains prognostic and predictive information
(Diakos et al., 2014; Gentles et al., 2015). Moreover, cancer
immunotherapy has revolutionized cancer treatment (Yang,
2015), illustrating that immune cells can be harnessed success-
fully to destroy tumors in a proportion of cancer patients.
Recently, studies have started to explore the cancer cell charac-
teristics—including the genetic makeup—that play a critical role
in dictating the heterogeneity in immune landscape between
different tumors. Studies aimed at assessing the link between
the genetics of human tumors and the immune infiltrate can be
roughly divided into three categories: (1) studies that have as-
sessed the extent of the mutational load of tumors with T cell
abundance, specificity and activity, (2) studies that have linked
distinct molecular tumor subtypes with a certain immune land-
scape, and (3) studies that have focused on the association be-
tween defined oncogenic driver mutations or loss of TSGs and
parameters of the inflammatory tumor microenvironment. In
this section, we will discuss the findings of these three different
strategies to assess the impact of genetic events on the cross-
talk with the immune system.
The core function of the adaptive immune system is to recog-
nize and destroy cells expressing non-self-antigens, while not
responding to self-antigens. Because cancers arise from host
cells, these cancer cells, with the exception of viral-associated
cancers, do not express the typical immunogenic foreign anti-
gens as seen in infections. The recent clinical breakthrough of
immune checkpoint inhibitors has fueled studies aimed at iden-
tifying the tumor antigens that are recognized by effective anti-
tumor immune responses. This resulted in the hypothesis that
a higher mutational load of a tumor will inevitably result in more
‘‘foreign’’ peptide presentation and consequently higher immu-
nogenicity of the tumor. Mutations and other genomic rearrange-
ments in cancer cells can encode for neo-antigens, antigens
uniquely expressed by the tumor, that when presented by
MHC molecules can potentially be recognized by the endoge-
nous T cell repertoire (Schumacher and Schreiber, 2015).
Indeed, neo-antigen-specific T cells have been observed in mel-
anoma patients (Lennerz et al., 2005; Linnemann et al., 2015;
Robbins et al., 2013; van Rooij et al., 2013; Wölfel et al., 1995)
and tumor types with a relatively high mutational burden, such
as melanoma, non-small cell lung cancer (NSCLC) and microsat-
ellite-instable (MSI) tumors display increased T cell influx and
have an overall better response rate to immunotherapeutics
compared to tumors with a lower mutational load (Le et al.,
2015; Rizvi et al., 2015; Van Allen et al., 2015). Nevertheless,
400 Immunity 48, March 20, 2018
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there is a substantial number of patients with good response
and low mutational load and vice versa (Balli et al., 2017;
Charoentong et al., 2017; Hugo et al., 2016; Rizvi et al., 2015;
Robinson et al., 2017; Spranger et al., 2016). These observations
suggest that for some tumors the mutational burden of tumors
can serve as a quantitative measure for T cell abundance and
likelihood to respond to immune checkpoint inhibitors. However,
there are clearly additional determinants of the immune contex-
ture in tumors besides mutational load.
Distinct molecular subtypes of human cancers can be associ-
ated with a defined immune composition and activation state in
the tumor microenvironment. Several cancer types can be
subtyped based on their molecular and genetic profile, thus
forming separate classes within a given tumor type, often with
distinct progression characteristics and treatment regimens.
For example, breast tumors can be classified as Luminal A
(ER/PR+, HER2–), Luminal B (ER/PR+, HER2+/–), HER2-enriched
(HER2+), and triple-negative/basal-like (ER/PR/HER2–) (Parker
et al., 2009). It has been reported that CD8+ T cells preferentially
infiltrate in triple negative tumors and those patients with high in-
tratumoral T cell abundance show better disease-free survival
(Chen et al., 2014; Medrek et al., 2012; Savas et al., 2016; Stan-
ton et al., 2016). Breast tumors that express hormone receptors
or HER2 are more frequently infiltrated by FoxP3+ regulatory
T cells (Tregs) compared to other subtypes, suggesting depen-
dency on these receptors in the establishment of an immuno-
suppressive milieu (Decker et al., 2012; Jiang et al., 2015).
Accordingly, the presence of Tregs in breast tumors predicted
metastatic progression and poor survival (Jiang et al., 2015;
Liu et al., 2011). For other cancer types, such as colorectal can-
cer, glioblastoma, and head and neck cancer, similar subtype-
specific tumor immune infiltrates have been observed (Becht
et al., 2016; Doucette et al., 2013; Keck et al., 2015; Wang
et al., 2017) (Table 1). These clinical observations indicate that
different molecular subtypes of tumors can be characterized
by distinct immune landscapes. However, due to the complex
nature that underlies molecular subtypes, the exact genes and
mechanisms that determine this immune heterogeneity cannot
be distilled from these studies.
A growing body of clinical observations indicates that defined
oncogenic driver mutations and loss of TSGs in human cancers
are also correlated with changes in immune composition and
immunotherapy response. For example, loss of NF1 in glioblas-
tomas associated with an increase in macrophages in the tumor
(Wang et al., 2017). Another study showed that loss of heterozy-
gosity (LOH) or mutation of TP53 in ER-negative and basal-like
breast tumors is associated with decreased intratumoral expres-
sion of a cytotoxic T cell signature and poor survival (Quigley
et al., 2015). These studies indicate that a single TSG can be
associated with the immune composition of the tumor, across
different tumor subtypes, and therefore might be a dominant
driving force of immune influx. Furthermore, in pancreatic ductal
adenocarcinoma (PDAC), expression of genes associated with
cytotoxic T cell function and immune checkpoint molecules
was inversely linked with amplification of MYC, NOTCH2, and
FGFR1, but not with mutational load (Balli et al., 2017). The
reduced expression of cytolytic immune response markers in
these MYC-, NOTCH2-, and FGFR1-amplified tumors was
observed across the different PDAC subtypes (Bailey et al.,
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Table 1. Clinical Observations on Tumor Subtype and Genotype-Immunophenotype Relations

Determinant of tumor immune Effect on therapy/disease
landscape Cancer type Immune cell subset outcome Reference
Tumor subtype
CMS1 CRC [ Cytotoxic T cellsa Overall favorable response (Becht et al., 2016)
to immune checkpoint blockade
Mesenchymal Glioblastoma [ Immunosuppressive NA (Doucette et al., 2013)
cellsa
[ T effector cellsa
[ Macrophages, (Wang et al., 2017)
neutrophilsa
Triple-negative/basal-like Breast cancer [ CD8+ T cells, High CD8+ T cell abundance (Chen et al., 2014; Medrek
macrophages gives high overall survival et al., 2012; Savas et al.,
2016; Stanton et al., 2016)
ER/PR/HER2+ [ Tregs High Treg abundance gives (Decker et al., 2012; Jiang
poor overall survival et al., 2015; Liu et al., 2011)
Inflamed/mesenchymal HPV+/– HNSCC [ CD8+ T cellsa NA (Keck et al., 2015)
Mutated oncogenes or tumor suppressor gene
TP53 loss or mutation ER– & basal-like Y Cytotoxic T cellsa Poor survival (Quigley et al., 2015)
breast cancer
Pan-cancer Y Cytotoxic T, NK cellsa NA (Rooney et al., 2015)
MYC, NOTCH2, FGFR1 PDAC Y Cytotoxic T cellsa NA (Balli et al., 2017)
amplification
MYC amplification Neuroblastoma Y T cellsa NA (Layer et al., 2017)

PIK3CA, MET mutations Pan-cancer [ Cytotoxic T, NK cellsa NA (Rooney et al., 2015)

BRAF mutations Thyroid cancer [ Immunosuppressive NA (Charoentong et al., 2017)
cellsa
RAS mutations [ T cellsa
VHL, STK11 mutations Pan-cancer Y Macrophagesa NA (Rooney et al., 2015)
NF1 loss Glioblastoma [ Macrophages NA (Wang et al., 2017)
Abbreviations: CRC, colorectal cancer. HNSCC, head and neck squamous cell carcinoma. PDAC, pancreatic ductal adenocarcinoma. NA, Not
assessed.
a
Immune cell composition based on gene expression signatures.

2016; Balli et al., 2017) and suggests that aberrant expression of
oncogenic pathways also dominantly impacts the composition
of the pancreatic tumor microenvironment (Table 1).
Genetic aberrations in tumors can also influence the T cell
response by altering expression levels of immune checkpoint
molecules by cancer cells. In a cohort of lung adenocarcinoma
patients, accumulation of p53 in tumor cells, which is indicative
of mutations in TP53, correlated with increased PD-L1 expres-
sion, while mutant EGFR tumors were characterized by low
expression of PD-L1 (Cha et al., 2016). In contrast, another study
showed that EGFR mutated lung tumors have high levels of PD-
L1 (Akbay et al., 2013), demonstrating that the role of mutant
EGFR in regulating PD-L1 expression is still under debate. In
metastatic neuroblastoma, amplification of MYCN correlated
with low expression of PD-L1 and a reduced T cell gene-expres-
sion signature in the tumor compared to MYCN-normal tumors
(Layer et al., 2017). Moreover, MYCN overexpression inversely
correlated with natural killer (NK) cell-activating factors such as
NKG2D in primary human neuroblastoma cell lines (Brandetti
et al., 2017). In addition, resistance to anti-PD-1 treatment in
melanoma and MSI CRC patients correlated with mutations in
JAK1/2 (Shin et al., 2017). Using human melanoma cell lines, it
was shown that JAK1/2 mutations led to an impaired IFN
signaling pathway-mediated PD-L1 expression, suggesting
that also JAK-STAT signaling is involved in regulating immune
checkpoint expression. These findings indicate that screening
for expression of certain oncogenes or loss of function of specific
TSGs might be exploited to improve the stratification of cancer
patients for therapeutic targeting the PD-1/PD-L1 axis.
The link between the genetic makeup of tumors and their im-
mune contexture was further strengthened by recent high-
throughput next generation sequencing (NGS) studies, which
allow an unbiased assessment of the genetics of tumors in par-
allel with high-resolution mapping of the tumor immune land-
scape. By correlating an RNA-based metric of immune cytolytic
activity (mainly associated with T and NK cell function) with ge-
netic data from the Cancer Genome Atlas (TCGA) dataset, it
was shown that immune activity varies substantially across tu-
mor types (Rooney et al., 2015). Consistent with the concept
that a higher mutational load increases tumor immunogenicity,
there was a positive correlation between adaptive immune acti-
vation gene signatures and mutational load across tumor types

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(Rooney et al., 2015). Interestingly, this study also revealed that
expression of genes associated with cytotoxic immune activa-
tion was elevated in tumors with mutations in PIK3CA or MET,
while TP53 mutant tumors displayed low levels of these genes
(Rooney et al., 2015). Additionally, mutations in VHL and
STK11 associated with reduced macrophage signatures (Roo-
ney et al., 2015). In another study into genotype-immunopheno-
type relationships, it was found that BRAF-mutated thyroid
tumors were characterized by infiltration of immunosuppressive
cells, while the RAS-mutated subtype contained higher T cell
influx and displayed downregulation of MHC molecules,
despite comparable mutational load (Charoentong et al., 2017).
Accordingly, oncogenic mutations also link with response to
immunotherapy. Using human datasets to predict response to
anti-CTLA-4 therapy in melanoma patients, it was demonstrated
that mutations in oncogenes such as KRAS, ATM, and mTOR
correlated with good immunotherapy response for some tumor
types (Ock et al., 2017). These studies demonstrate that NGS
studies can reveal relationships between cancer-associated
genes, activation of immune cells and response to immunother-
apies in a high-throughput and high-resolution manner.
Together, these observations suggest that mutational load, tu-
mor subtype, and aberrant expression of oncogenes and TSGs
highly impact the tumor microenvironment. Interestingly, for
certain tumors, the tumor driver genes, mutational load, and sub-
type are intrinsically linked, as for example aberrant expression
of BRCA1 impairs the DNA damage repair machinery and there-
fore has consequences for the mutational load of a tumor.
However powerful, these genotype-immunophenotype studies
in human cancers leave several questions open. Due to the
descriptive nature of these analyses, these studies do not yield
mechanistic insights into causal relationships between tumor
genetics and the immune composition. From a therapeutic
perspective, it is important to assess whether a causal link be-
tween tumor genetics and immune contexture exists and to
elucidate the underlying molecular mechanisms, since this
would open new avenues for personalized immune intervention
strategies. Of note, the above described clinical studies often
rely on the analysis of a small tumor biopsy at a given time point,
and therefore may overlook intratumoral heterogeneity and tu-
mor evolution. For these reasons, mechanistic studies in relevant
GEMMs that mimic the development, heterogeneity and pro-
gression of human tumors in an immune-proficient setting are
key to understand how cancer cell-intrinsic properties can
dictate the tumor immune landscape (Kersten et al., 2017). In
the next sections, we will discuss recent insights into these
mechanisms and how these insights can be translated into
personalized immune intervention strategies. Given the growing
interest in the role of the immune system in tumorigenesis, we
anticipate that more pathways will be uncovered in the years
to come.
NF-kB and p53: Central Nodes in Cancer Cell-Mediated
Changes in the Inflammatory Microenvironment
The mechanisms by which oncogenes and TSGs orchestrate
the inflammatory tumor microenvironment are now being uncov-
ered. Specific cancer-associated genes, besides driving cancer
cell-intrinsic programs, also change the secretome of cancer
cells and thereby change the immune microenvironment
402 Immunity 48, March 20, 2018
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(Figure 1, Table 2). One notable example is NF-kB, a transcrip-
tion factor that controls cell survival and proliferation, but also
production of inflammatory cytokines. For example, NF-kB
signaling promoted tumor development in the KrasLSL-G12D/+;
Trp53F/F lung adenocarcinoma model (Meylan et al., 2009). Inter-
estingly, NF-kB activity was increased upon loss of p53, and
restoration of p53 expression reduced its activity. Cancer cell-
intrinsic NF-kB inactivation resulted in increased intratumoral
immune cell influx and impaired lung cancer formation in
KrasLSL-G12D;Trp53F/F mice (Meylan et al., 2009), showing a link
between loss of p53, NF-kB pathway activation, and an inflam-
matory tumor microenvironment. As one of the most frequently
mutated genes in cancer (Kastenhuber and Lowe, 2017), the tu-
mor suppressor p53 can potentially regulate the immune infil-
trate in a wide variety of tumor types, through its interactions
with NF-kB or otherwise. Indeed, the control of the pro-inflam-
matory NF-kB pathway by p53 appears to be occurring across
cancer types (Cooks et al., 2014). For example, in the Pgr-
cre;Cdh1F/F;Trp53F/F mouse model for endometrial cancer, the
combined loss of E-cadherin and p53 resulted in increased
NF-kB activity, which correlated with elevated cytokine expres-
sion and increased influx of macrophages, as compared to dele-
tion of either gene alone (Stodden et al., 2015). However, in
another mouse model in which endometrial tumorigenesis is
driven by loss of PTEN, loss of p53 did not alter neutrophil influx
into early lesions (Blaisdell et al., 2015), suggesting that this ef-
fect might be context dependent. Together, these and other
studies show that NF-kB, key regulator of immune signaling in
the tumor microenvironment, is controlled by p53. In several tu-
mor models, loss of p53 activates the NF-kB pathway, stimu-
lates the production of cytokines and other pro-inflammatory
mediators from cancer cells, which through paracrine interac-
tions modify the immune contexture.
Studies in mouse models in which chemical-induced inflam-
mation drives malignant conversion and progression show that
the NF-kB-mediated inflammatory response can also be a
driving force of tumorigenesis in p53-knockout models. For
example, azoxymethane (AOM)-induced colonic tumorigenesis
was enhanced in Villin-cre;Trp53F/F mice that harbor p53 dele-
tion in intestinal epithelial cells, as compared to mice with p53
proficient intestinal epithelial cells (Schwitalla et al., 2013). Mech-
anistic studies in these mice revealed that loss of p53 impaired
the removal of pre-neoplastic transformed cells and induced
NFkB-dependent cytokine production, thus driving an inflamma-
tory tumor microenvironment (Schwitalla et al., 2013). Impor-
tantly, genetic ablation of IKKb, a protein involved in NF-kB
activation, in cancer cells or myeloid cells, reduced tumor prolif-
eration and invasion, demonstrating that NF-kB signaling in p53
null cancer cells or in surrounding myeloid cells plays a funda-
mental role in tumor progression (Schwitalla et al., 2013).
A critical feature of p53 biology in cancer not addressed in
these studies is its wide variety of both activating and inactivat-
ing mutations, leading to very diverse and sometimes even
opposing functions (Muller and Vousden, 2014). How one of
these p53 mutations affects NF-kB activation, was addressed
in a gain-of-function (GOF) mutant p53G515A mouse model that
was repeatedly exposed to dextran sodium sulfate (DSS) to stim-
ulate colitis-induced colorectal cancer (CRC) (Cooks et al.,
2013). Repair of DSS-induced damaged tissue was impaired in
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Figure 1. Cancer Cell-Intrinsic Signaling
A B C Pathways that Shape the Tumor Immune
Landscape
(A) The p53 pathway can modulate the immune
microenvironment of the tumor by regulating NF-kB
signaling, that is generally activated by loss or loss-
of-function (LOF) mutation of p53. This results in
increased cytokine production by tumor cells and
recruitment and activation of immune cells, such as
macrophages (Cooks et al., 2013; Schwitalla et al.,
2013). In addition, by activating ROS, mutant p53
can induce JAK-STAT signaling and thereby in-
crease macrophage, neutrophil, and CD4+ T cell
frequencies in the tumor, while concurrently
reducing CD8+ T cell levels (Wörmann et al., 2016).
D (B) Mutant KRAS can increase GM-CSF by can-
cer cells and thereby promote neutrophil recruit-
F ment to the tumor (Pylayeva-Gupta et al., 2012).
(C) Activated Notch signaling can signal to
E monocytes and macrophages by driving CCL2
G and IL-1b expression. Notch also drives TGF-b
receptor and uPA expression, of which the latter
is involved in activating macrophage-derived
TGF-b, thus inducing a growth promoting
H K signaling loop (Shen et al., 2017). Notch can also
I J limit the anti-tumor immune response by inhibiting
C/EBPb and thereby limiting expression of IL-1,
IL-6, and IL-8 (Hoare et al., 2016).
(D) Loss of tumor suppressor gene LKB1 can
drive production of G-CSF, CXCL7, and IL-6 by
the tumor, which promotes neutrophil recruit-
ment, which can block anti-tumoral cytotoxic
T cells (Koyama et al., 2016).
(E) ZBTB7a blocks CXCL5 production by binding
its promoter, and loss of ZBTB7a therefore can
lead to CXCL5-mediated neutrophils recruitment
(Bezzi et al., 2018).
(F) High mutational load in tumors can increase
the number of neo-antigens and thus potentially
increase neo-antigen-specific T cell responses.
(G) PTEN can negatively regulate NF-kB signaling. Therefore, loss of PTEN increases NF-kB-mediated expression of cytokines and growth factors that drive
macrophage, neutrophil, and Treg accumulation in the tumor (Ying et al., 2011).
(H) MYC can regulate macrophage recruitment, which is promoted by p53 loss (Yetil et al., 2015). Additionally, by inducing CCL5 and IL-1b, MYC can promote
mast cell recruitment and activation (Shchors et al., 2006; Soucek et al., 2007). MYC can also induce CCL9 and IL-23 expression, the former of which induces
macrophage recruitment, while the latter limits NK, T, and B cell accumulation in the tumor (Kortlever et al., 2017). MYC can also inhibit CD4+ T cells and
macrophages by regulating PD-L1 and CD47 expression on tumor cells (Casey et al., 2016). Lastly, the anti-tumor NK- and CD8+ T cell-response to MYC
amplified tumors can be counteracted by additional loss of p53 in the tumor, while amplification of Bcl-2 promotes anti-tumor immunity (Schuster et al., 2011).
(I) SMAD4 can suppress YAP1 signaling, and loss of SMAD4 in tumors therefore drives YAP1-mediated CXCL5 production, which recruits immunosuppressive
neutrophils (Wang et al., 2016).
(J) PRKCI amplification can also induce YAP signaling. Activation of YAP1 here induces TNFa-mediated recruitment and activation of immunosuppressive
neutrophils (Sarkar et al., 2017).
(K) Activated Wnt signaling via b-catenin can limit the priming of CD8+ T cells by suppression of CCL4 production, which would otherwise activate CD103+ DCs
(Spranger et al., 2015).

p53G515A mice. Combined with enhanced NF-kB activity and
extended inflammation, this led to an increase in colorectal tu-
mor incidence in mice (Cooks et al., 2013). In addition,
p53G515A mutant intestinal organoids derived from these mice
showed increased tumor necrosis factor alpha (TNF-a) and
CXCL1 production when compared to p53–/– cells, which could
be reverted by NF-kB knockdown (Cooks et al., 2013). In line
with these experimental findings, expression of mutant TP53
correlated with NF-kB expression in human CRC patients
(Cooks et al., 2013). These findings show that this GOF mutant
p53 induces aberrant NF-kB interactions, leading to different in-
flammatory phenotypes than observed after loss of p53. In a
mouse model for pancreatic cancer, p53R172H has been re-
ported to elicit similar immune phenotypes as loss of p53.
KrasG12D;p53R172H mutant mouse pancreatic tumors drive in-
flammatory responses via ROS and JAK2-STAT3 activation
(Wörmann et al., 2016). Here, both p53R172H mutant and p53-de-
fiencient tumors displayed similar STAT3-dependent immune
evasion and accelerated tumor growth, which both could be
reversed by pharmacological targeting of JAK-STAT signaling
(Wörmann et al., 2016). These findings indicate that different mu-
tations of p53 can shape the tumor microenvironment in a
distinct manner. In future studies, it would be interesting to sys-
tematically dissect the differences between gain- and loss-of-
function p53 mutations on NF-kB interactions and the immune
landscape of the tumor. Altogether, these studies demonstrate
the profound role of p53-mediated regulation of key immune
signaling pathways such as NF-kB and STAT signaling, and its
downstream effects on the tumor immune landscape.
MYC: A Key Controller of the Immune Microenvironment
The MYC oncogene is one of the most frequently amplified onco-
genes in several tumor types, such as lymphoma, breast cancer,
and NSCLC (Beroukhim et al., 2010). As a transcription factor,

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Table 2. Genetic Aberrations Influencing the Immune Landscape of Tumors

Genetic Consequence for
Gene aberration intratumoral immune cells Signaling involved Tumor type Tumor model Reference
AKT Loss Macrophages Y AKT deletion decreases tumorigenesis by reducing Liver cancer Alb-cre;PtenF/F and (Debebe et al., 2017)
pro-tumorigenic Wnt-producing macrophages in Alb-cre;PtenF/F;Akt2F/F
the tumor
ATR Deletion Macrophages [ NA Melanoma Tyr::ERT2;BrafV600E/+;PtenF/F (Chen et al., 2017)
B cells [, CD8 T cells Y
+ and Tyr::ERT2;BrafV600E/+;
PtenF/F;ATRF/F
b catenin Amplification CD8+ T cells Y Active b-catenin inhibits CCL4, thus inhibiting Melanoma Tyr:cre-ER;BrafLSL-V600E/+; (Spranger et al., 2015)
CD8+ T cell priming by CD103+ DCs. PtenF/F and Tyr:cre-ER;
BrafLSL-V600E/+;PtenF/F;
LSL-CAT-STA
CKIa Loss Macrophages Y Loss of CKIa triggers an inflammatory SASP. CRC Villin-cre;CKIaF/F, Villin-cre; (Pribluda et al., 2013)
Subsequent loss of p53 or p21 leads to CKIaF/F;p21 / and Villin-
inflammation-accelerated tumorigenesis. cre;CKIaF/F;Trp53F/F
EGFR Mutation Macrophages, neutrophils [ NA NSCLC Ccsp-rtTA;TetO-EgfrL858R (Busch et al., 2016)
CD8 T cells Y
+

CD8+ T cells Y EGFR pathway activates PDL1 expression in Ccsp-rtTA;TetO-EGFRT790M, (Akbay et al., 2013)
bronchial epithelial cells EGFRT790M/L858R and
EGFRexon 19 del/T790M
FAK Amplification Macrophages, neutrophils, Potentially via STAT3 signaling. PDAC p48-Cre;KrasLSL-G12D/+ (Jiang et al., 2016)
monocytes [
CD3+ T cells Y, Tregs [ Potentially due to immunosuppressive
myeloid cells
FGFR Activation Neutrophils [ FGFR drives mTOR signaling, which causes Breast cancer MMTV-Wnt1, MMTV-Wnt1- (Welte et al., 2016)
increase in G-CSF production, driving neutrophil iFGFR and MMTV-cre;
expansion, thus promoting tumor progression Trp53F/F;PtenF/F
IFNAR1 Mutation NK cells Y, neutrophils [ Inactivating mutant of IFNAR1 promotes the CRC AOM-DSS induced (Katlinski et al., 2017)
CD8+ cells Y establishment of an immunosuppressive
microenvironment and tumor progression
KRAS Mutation Myeloid cells [ NA NSCLC KrasLSL-G12D/+ and (Busch et al., 2016)
+
T cells (CD8 , Treg, gd KrasLSL-G12D/+;Trp53F/F
T cells) [
LKB1 Loss Neutrophils [, Macrophages, Loss of Lkb1 leads to an increase in CXCL7, NSCLC KrasLSL-G12D/+ and (Koyama et al., 2016)
CD4+, CD8+ T cells Y G-CSF and IL-6, which drive neutrophil increase. KrasLSL-G12D/+;Lkb1F/F
Neutrophils decrease IFNg+ T cells in the tumor.

Review
mTOR Amplification NK cells, macrophages [ mTOR regulates IL-1a levels, and IL-1a activates Liver cancer Hydrodynamic tail-vein (Herranz et al., 2015;
NFkB, thus driving SASP and immune cell injection of NRASG12V Laberge et al., 2015)
recruitment
T, B cells [ mTOR activates tumor suppressive SASP

Immunity
(Continued on next page)
 Review
Immunity
Table 2. Continued
Genetic Consequence for
Gene aberration intratumoral immune cells Signaling involved Tumor type Tumor model Reference
MYC Loss Macrophages, neutrophils Y NA Pancreatic cancer RIP1-Tag2 and TRE- (Sodir et al., 2011)
Omomyc;CMVrtTA;RIP1-
Tag2
Amplification Mast cells [ MYC activation drives IL-1b and CCL5 Pancreatic cancer pIns-mycERTAM;RIP7- (Shchors et al., 2006;
expression, leading to an influx of mast cells bcl-xL Soucek et al., 2007)
in the pancreatic tumor
CD4+ T cells Y Regulates expression of CD47 and PDL1 T-ALL MYC T-ALL s.c. (Casey et al., 2016)
transplanted cell line, Em-
tTA/tet-O-MYC, LAP-tTA/
tet-O-MYC
Macrophages [ NK cells Y MYC drives expression of CCL9, which recruits NSCLC KrasLSL-G12D;Rosa26-LSL- (Kortlever et al., 2017)
macrophages, and IL-23, which limits NK MycERT2
recruitment
T, B cells Y MYC drives expression of IL-23, which excludes
T and B cells from the tumor
NOTCH Amplification Macrophages [ NOTCH activates CCL2 and IL-1b production by Breast cancer 4T1, MDA-MB-231 cell (Shen et al., 2017)
tumor cells thus increasing pro-tumoral monocytes lines and RBPJkIND-
and macrophages MMTV;MMTV-PyMT
T cells Y NOTCH represses CEBP/b leading to impaired Liver cancer Hydrodynamic tail-vein (Hoare et al., 2016)
clearance of senescent cells and subsequent injection of NRASG12V
liver tumor development
NRAS Mutation Neutrophils, monocytes, NRAS mutation induces SASP, thus recruiting Liver cancer Hydrodynamic tail-vein (Kang et al., 2011)
NK cells, macrophages, immune cells and CD4+ T cell-mediated injection of NrasG12V
DCs [ clearance of tumor cells. and NrasG12V/D38A
CD4+ T cells [ NRAS-induced senescent cells are cleared by
CD4+ T cells
p53 Mutation Myeloid cells [ Mutant p53 activates NFkB and thus drives CRC DSS-induced (Cooks et al., 2013)
cytokine production and inflammation-
associated tumor progression
Loss Neutrophils, macrophages [ Potentially via dysregulation of NFkB Lung cancer KrasLSL-G12D/+ and (Meylan et al., 2009)
KrasLSL-G12D/+;Trp53F/F
Immunity 48, March 20, 2018 405

Macrophages [ Loss of p53 leads to an impaired intestinal epithelial CRC Villin-creERT2;Trp53F/F (Schwitalla et al., 2013)
barrier, thus triggering intestinal microflora- and AOM-induced
mediated immune activation via NFkB.
Macrophages, monocytes, STAT3-mediated establishment of an PDAC Ptfa1-cre;KrasLSL-G12D/+, (Wörmann et al., 2016)
neutrophils [ immunosuppressive microenvironment Ptfa1-cre;KrasLSL-G12D/+;
p53F/F and Ptfa1-cre;
KrasLSL-G12D/+;p53R172H/+
Monocytes [ p53 transcriptionally regulates CXCL17, and loss Prostate cancer Pb-cre;Pten F/F;Trp53F/F (Bezzi et al., 2018)
of p53 leads to an increase of CXCL17, thus
recruiting monocytes to the tumor
(Continued on next page)
406 Immunity 48, March 20, 2018

Table 2. Continued
Genetic Consequence for
Gene aberration intratumoral immune cells Signaling involved Tumor type Tumor model Reference
PRKCI Amplification NK cells Y, CD11b+Gr1+ PRKCI activates YAP1, inducing TNFa to promote High-grade Pax8-cre;tetOLSL-PRKCI; (Sarkar et al., 2017)
cells [ an immunosuppressive microenvironment serous ovarian PtenF/F;Trp53F/F with
CD8+ T cellsY PRKCI amplification induces immunosuppressive carcinoma inducible loss of PRKCI
neutrophils, thus reducing CD8+ T cells and cell lines derived
from these tumors
PTEN Loss CD11b+Gr1+ cells [ PTEN loss activates NFkB and thereby expression PDAC p48-Cre; KrasLSL-G12D; (Ying et al., 2011)
of CXCL1, G-CSF, IL-23 PtenF/+
CD8+ T cells Y Loss of PTEN promotes resistance to T cell killing Melanoma Cell line inoculation (Peng et al., 2016)
by inhibiting autophagy models and Tyr:CreER;
PtenF/F;Braf V600E/+
RAS Mutation CD11b+Gr1+ cells [ Via GM-CSF production by tumor cells PDAC KrasG12D inoculation (Ancrile et al., 2007;
model Pylayeva-Gupta et al.,
2012)
RB Loss Macrophages Y NA SCLC Rb1F/F;Trp53F/F (Busch et al., 2016)
SMAD4 Loss Neutrophils [ SMAD4 loss increases YAP1-mediated CXCL5 Prostate cancer Pb-cre;PtenF/F;Trp53F/F (Wang et al., 2016)
expression, thus driving immunosuppressive
neutrophils.
CD8+ T cells, Tregs Y PRKCI amplification induces immunosuppressive
neutrophils, thus reducing CD8+ T cells and Tregs
ZBTB7a Loss Neutrophils [ p53 transcriptionally regulates SOX-9, and loss of Prostate cancer Pb-cre;Pten F/F;Trp53F/F (Bezzi et al., 2018)
p53 leads to an increase of SOX-9, which in turn
activates CXCL5, thus recruiting neutrophils to
the tumor
Abbreviations: NA, Not assessed. SASP, Senescence-associated secretory phenotype. CRC, Colorectal cancer. NSCLC, Non-small cell lung cancer. PDAC, Pancreatic ductal adenocarcinoma.
T-ALL, T cell acute lymphoblastic leukemia. SCLC, small cell lung carcinoma.
Listed here are the cancer cell-intrinsic genetic aberrations that result in a change in innate and adaptive immune contexture as demonstrated in genetically engineered mouse models.

Review
Immunity
Immunity
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MYC regulates many essential processes in the cell. In addition,
recent studies revealed that it also has a strong hold on the
tumor immune landscape (Figure 1, Table 2). Using the RIP1-
Tag2;TRE-Omomyc;CMV-rtTA pancreatic b-cell cancer mouse
model, in which treatment with doxycyclin induces expression
of a dominant-negative MYC mutant, it was shown that inhibition
of endogenous MYC in established islet tumors resulted in tumor
regression, which was accompanied by a marked decrease in
infiltrating macrophages and neutrophils (Sodir et al., 2011).
This study illustrates that although MYC is not an oncogenic
driver in this tumor model, its endogenous expression is crucial
for tumor progression and has a profound effect on the inflam-
matory microenvironment. In another transgenic b-cell cancer
mouse model carrying a switchable form of the MYC oncopro-
tein in the pancreas, forced expression of MYC in b-cells resulted
in pancreatic cancer formation (Shchors et al., 2006). Impor-
tantly, Myc activation stimulated production of the potent pro-in-
flammatory cytokines CCL5 and interleukin-1b (IL-1b) by b cells,
which facilitated tumor angiogenesis and recruitment of pro-
tumoral mast cells to the tumor (Shchors et al., 2006; Soucek
et al., 2007). These studies demonstrate that MYC can drive
tumor progression at least in part through orchestrating pro-
tumoral inflammatory conditions.
The effects of MYC signaling on the tumor microenvironment
may not be limited to pancreatic cancer alone. In the Em-tTA-
TRE-Myc mouse lymphoma model, inactivation of MYC in estab-
lished tumors resulted in a marked decrease in intratumoral
macrophages (Yetil et al., 2015). It would be of interest to assess
whether the same MYC-controlled inflammatory mediators are
involved in lymphoma and pancreatic cancer. Interestingly,
upon additional loss of p19ARF, but not p53, MYC-dependent
regulation of macrophage recruitment is not observed (Yetil
et al., 2015), suggesting that the ability of MYC to control recruit-
ment of immune cells to tumors can be counteracted by other
aberrantly expressed genes. This is also illustrated by the obser-
vation that the spontaneous anti-tumor T and NK cell response in
the Em-MYC lymphoma model could only be elicited when Bcl-2
was overexpressed, but not when p53 was deleted (Schuster
et al., 2011). How p53 loss counteracts MYC activity in modu-
lating the tumor microenvironment however remains a subject
of future research.
MYC can also control the immune landscape of tumors by
regulating expression of immune checkpoint molecules. In the
Em-tTA/tet-O-MYC lymphoma model and cell lines with switch-
able MYC expression, MYC increased the expression of both
PD-L1 and the ‘‘don’t eat me’’ receptor CD47 on cancer cells
by binding directly to their respective promoters (Casey et al.,
2016). Exogenous overexpression of PD-L1 and CD47 on cancer
cells limited the CD4+ T cell and macrophage recruitment to the
tumor. Moreover, MYC inactivation downregulated CD47 and
PD-L1 expression and induced tumor regression, while exoge-
nous overexpression of PD-L1 and CD47 in cancer cells
enhanced disease progression (Casey et al., 2016). Although
not experimentally proven, this study suggests that MYC may
facilitate tumor immune escape by induction of immune check-
points. Similarly, a MYC amplification-dependent T cell-poor
environment has also been reported in human neuroblastomas,
but in these tumors genomic amplification of N-MYC inversely
correlated with PD-L1 expression, possibly due to MYC-induced
suppression of interferons and pro-inflammatory signaling path-
ways (Layer et al., 2017). These studies show that MYC activa-
tion in tumors can control immune checkpoint molecules and
T cell influx, but the underlying mechanisms may differ between
tumor types.
Another mechanism by which MYC regulates the immune
phenotype of tumors was recently demonstrated in the
KrasG12D-driven lung adenocarcinoma model. Here, conditional
MYC amplification resulted in a rapid decrease of intratumoral B,
T, and NK cells, and an increase in macrophages (Kortlever et al.,
2017). Mechanistically, MYC amplification led to increased
expression of IL-23 by cancer cells, which inhibited B, T, and
NK cell recruitment, and increased expression of CCL9, which
recruited and activated macrophages in the tumor. These mac-
rophages inhibited T cells, while also promoting angiogenesis.
Interestingly, these tumors rapidly acquired dependency on
MYC amplification, and MYC de-activation resulted in tumor
regression in an NK cell-dependent fashion (Kortlever et al.,
2017). These findings suggest that targeting MYC in tumors
would be an attractive therapeutic strategy to unleash anti-tumor
immunity. While MYC is as of yet not directly targetable, indirect
therapeutic strategies emerge. One such strategy targets the
epigenetic modulators DNA methyl transferases (DNMTs) and
histone deacetylases (HDACs). Combined treatment of NSCLC
mouse models with DNMT and HDAC inhibitors reduced MYC
expression, increased CCL5 levels, decreased macrophage
influx, and increased cytotoxic T cell influx and inhibited tumor
growth (Topper et al., 2017). This study demonstrates that indi-
rect targeting of MYC might prove therapeutically beneficial by
limiting tumor growth and reversing immune evasion. However,
this study did not formally exclude a direct effect of the epige-
netic modulators on the immune system.
These studies show that in addition to the key role MYC has in
tumor cell-intrinsic processes, this transcription factor can exert
a wide variety of functions to modulate both the innate and the
adaptive immune landscape of several tumor types. While
MYC is not directly targetable, insights into these mechanisms
open up new ways to target MYC-regulated signaling.
Other Genetic Determinants of the Tumor Immune
Landscape
The effect of oncogenes and TSGs on the tumor immune land-
scape is not just limited to the abovementioned genes and path-
ways; several other genetic events and downstream immune
effects have been described (Figure 1, Table 2). One example
is the impact of the Ras oncogene on tumor-associated myeloid
cells. Mutated Ras strongly induces expression of IL-6 and IL-8
in in vitro models (Ancrile et al., 2007; Sparmann and Bar-Sagi,
2004). These Ras-controlled cytokines have been reported to
facilitate myeloid cell infiltration and tumor progression (Ancrile
et al., 2007; Sparmann and Bar-Sagi, 2004). Furthermore,
KrasG12D-induced changes in cytokine expression resulted in
accumulation of CD11b+Gr1+ immunosuppressive cells in a
variety of tumor models, including pancreatic and lung cancer
(Ji et al., 2006; Pylayeva-Gupta et al., 2012; Wislez et al.,
2006). Ablation of one of the KrasG12D-induced cytokines, GM-
CSF, in tumor cells impaired immunosuppressive cells from
entering pancreatic tumors and consequently resulted in an in-
crease in CD8+ T cells (Pylayeva-Gupta et al., 2012). These
Immunity 48, March 20, 2018 407

studies demonstrate the causal relationship between Ras onco-
genic signaling pathways, immune-stimulatory transcription pro-
grams and immune landscape. Another study revealed a role for
adherence junction protein a-catenin in inflammatory signaling.
In the K14-Cre;a-cateninF/F mouse model for skin squamous
cell carcinoma (SCC), loss of a-catenin activates NFkB and
its downstream inflammatory target genes, such as IL-1b and
IL-6, and stimulates SCC, thus again linking tumor-initiating
oncogenic events with NF-kB-mediated immune signaling (Ko-
bielak and Fuchs, 2006). Likewise, by comparing the Pdx1-
cre;KrasLSL-G12D and the Pdx1-cre;KrasLSL-G12D;Pten+/F mouse
models for pancreatic cancer, it was demonstrated that loss of
Pten resulted in increased activation of the NF-kB pathway,
driving expression of several immune regulators by cancer cells,
such as G-CSF, IL-23 and CXCL1 (Ying et al., 2011). Pten loss
and the downstream NF-kB activation not only accelerated tu-
mor progression, but also influenced the frequency of intratu-
moral neutrophils, monocytes, and Tregs (Ying et al., 2011).
Another study showed a profound role for the STK11/LKB1
tumor suppressor in NSCLC. Comparing KrasG12D/+ with
KrasG12D/+;Lbk1 / mice, it was found that loss of Lkb1 resulted
in increased IL-6 production, which resulted in higher intratu-
moral and systemic immunosuppressive neutrophil levels
(Koyama et al., 2016). Indeed, blockade of IL-6 resulted in
increased levels cytotoxic CD8+ T cells and tumor control
(Koyama et al., 2016). Although not all of these studies eluci-
dated the functional consequence of the altered immune land-
scape on tumor growth, they demonstrate that a wide variety
of cancer-driving mutations can dictate the composition of the
tumor microenvironment.
Collectively, studies pertaining to cancer cell-intrinsic path-
ways and immune contexture are gaining ground and have iden-
tified various cancer-driving genes that orchestrate diverse
immune landscapes in the tumor. Thus far, many of these studies
have been relatively biased and focused on a single genetic
pathway in a single mouse tumor model. A more systematic
assessment of immune cell populations in relation to tumor
genotypes was recently performed in two studies. One com-
pared four independent lung cancer GEMMs: Ccsp-rtTA;TetO-
EgfrL858R, Rb1F/F;Trp53F/F, KrasLSL-G12D/+ and KrasLSL-G12D/+;
Trp53F/F models, representing molecularly distinct human
SCLC and NSCLC subtypes (Busch et al., 2016). This approach
revealed key differences in immune cell content between the
different tumor genotypes, such as that EgfrL858R-driven tumors
showed lower frequencies and activation of CD8+ T cells
compared to Kras-driven tumors, whereas NK cells in Kras-
driven tumors, but not EGFR mutants, show downregula-
tion of activation markers (Busch et al., 2016). A second
study compared the Pb-cre;PtenF/F;Zbtb7aF/F, Pb-cre;PtenF/F;
Trp53F/F and Pb-cre;PtenF/F;PmlF/F prostate cancer models
and observed profound differences in composition of the tumor
microenvironment (Bezzi et al., 2018). Mechanistic studies re-
vealed distinct chemokine production by tumors controlled by
loss of Zbtb7a, p53, or Pml and blockade of the respective
signaling pathways impaired innate immune cell recruitment
and tumor progression. These studies demonstrate the powerful
potential of GEMMs in identifying the complex mechanisms that
control the tumor microenvironment and potential for immuno-
modulatory therapeutic intervention based on genetic aberra-
408 Immunity 48, March 20, 2018
Immunity
Review
tions in the tumor. With the rapid developments in mouse
model-generating techniques (Huijbers, 2017), future systematic
approaches in GEMMs may increasingly reveal causal geno-
type-immunophenotype relationships, and its impact on tumor
progression.
The Role of Oncogene-Induced Senescence in
Promoting an Inflammatory Tumor Microenvironment
A cancer-cell-intrinsic pathway in which many of the above-
mentioned cancer-driving genes are involved and that strongly
influences the intratumoral immune landscape is cellular senes-
cence. In a process called oncogene-induced senescence (OIS),
precancerous cells undergo cell-cycle arrest upon activation of
oncogenic signaling. Cellular senescence is a physiological pro-
gram that can be activated in response to cellular stress and ag-
ing, leading to an essentially irreversible cell proliferation arrest
(Muñoz-Espı́n and Serrano, 2014). Senescent cells can persist
and actively secrete cytokines and other inflammatory and
growth-promoting factors, a process called the senescence-
associated secretory phenotype (SASP) (Pérez-Mancera et al.,
2014). Through their SASP, senescent cells can exert a signifi-
cant, and sometimes opposing, impact on the immune land-
scape of the tumor. SASP can lead to immune-mediated
clearance of pre-malignant cells, or via stimulation of chronic
inflammation promote tumor progression. Below we discuss
how oncogenes and TSGs, via SASP activation, shape the in-
flammatory microenvironment.
Several oncogenes and TSGs have been linked with SASP
activation (Figure 2). The p53 pathway plays an important role
in the induction of OIS. This was demonstrated by the induction
of senescence and tumor clearance upon doxycyclin-mediated
activation of p53 in a HrasG12V;TRE.shp53 inoculation model
for liver cancer (Xue et al., 2007). Activation of p53 did not lead
to tumor cell death in a cell-autonomous manner, but rather neu-
trophils, macrophages and NK cells were recruited to these tu-
mors by activated SASP and removed the senescent cells (Xue
et al., 2007). Indeed, maintenance of WT p53 was a prerequisite
of senescence induction, as also observed in other tumor
models (Cooks et al., 2013; Pribluda et al., 2013). Because
NF-kB is a key transcription factor in SASP activation (Chien
et al., 2011), the regulation of NF-kB by the p53 pathway might
play an important role in SASP regulation. In colorectal tumor
models, Wnt signaling can also regulate SASP induction. Villin-
creERT2;CKIaF/F mice, which display hyper-activated Wnt
signaling due to loss of CKIa, exhibit growth arrest of colorectal
tumors and induction of senescence, paired with an inflamma-
tory response (Pribluda et al., 2013). SASP is maintained upon
additional p53 deletion in this model, however, it dissociates
from growth arrest while the inflammatory response continues,
resulting in inflammation-accelerated tumorigenesis (Pribluda
et al., 2013). These findings illustrate that depending on the
genetic makeup of cancer cells, the senescence-associated in-
flammatory response can result in two opposing outcomes: tu-
mor inhibition or tumor promotion. In addition to p53 and Wnt,
mTOR signaling was shown to induce SASP in CRC and prostate
cancer cells in vitro (Laberge et al., 2015). mTOR inhibition by ra-
pamycin decreased mTOR-induced SASP and decreased influx
of macrophages, T, B, and NK cells into inoculated NrasG12V
mutant liver tumors (Herranz et al., 2015). These studies suggest
Immunity
Review
A Rasmut B Legend
p53WT MYC
mTOR
Wntactive
NF B
STAT3
Notchlow Senescence-associated
Non-senescent secretory phenotype
malignant cell
Immune-mediated
clearance of
senescent cells
Senescent cell
that targeted therapies, such as rapamycin, may reduce tumor-
induced inflammation, but potentially also reduce senescent
tumor cell clearance by infiltrating immune cells, thus demon-
strating the complexity of targeting SASP. Nonetheless, these
studies reveal the essential role of oncogenes and TSGs in
SASP induction and the potential of targeting these genes to
revert tumor-promoting SASP.
The composition of SASP mediators secreted by senescence
cells is dynamic and experimental evidence points toward
NOTCH1 as one of the master regulators controlling this SASP
diversity. In NrasG12V mutant tumor models, NrasG12V-induced
senescence was accompanied by fluctuations in endogenous
Notch expression levels (Hoare et al., 2016). Ectopic expression
of active Notch in an NrasG12V-dependent oncogene-induced
senescence liver model increased cancer progression in a
non-cell-autonomous fashion (Hoare et al., 2016). In this model,
Notch levels determined the composition of the SASP and sub-
sequent immune function. Notch inhibited lymphocyte-mediated
clearance of senescent cells through repression of C/EBPb.
Reversely, inhibition of Notch during senescence led to an in-
crease of lymphocyte-mediated senescent cell clearance (Hoare
et al., 2016). This Notch-dependent cytokine production and
shaping of the immune phenotype of tumors was also demon-
strated in breast cancer, where tumor-intrinsic Notch signaling
increased monocyte and macrophage accumulation by in-
creasing expression of IL-1b and CCL2 (Shen et al., 2017). These
studies demonstrate that immune cell influx can be strongly
influenced by SASP, but also that the activity of cancer cell-
intrinsic genes play important roles in determining the spectrum
of inflammatory mediators produced within the tumor. Indeed, in
the Ptf1a-cre;KrasLSL-G12D/+ mouse model for pancreatic cancer,
genetic deletion of RelA, the gene that encodes the NF-kB sub-
unit p65, abrogated senescence and SASP, thus enhancing pro-
gression of pancreatic tumors (Lesina et al., 2016). While
reducing SASP, RelA deletion led to a marked increase in
immunosuppressive cells and decreased T cell activation in
the pancreata of these mice (Lesina et al., 2016). Therefore,
in these tumors, the cancer-immune cell crosstalk is not limited
to SASP.
The infiltrating immune cells can also impact senescence it-
self. In Pten-induced senescent prostate tumors, CD11b+Gr-1+
Figure 2. Relationship between Genetic
Events in Cancer Cells, the Dynamic
Ras mut
Aspects of SASP and the Immune System
p53LOF
NK cell (A) Oncogene-induced senescence (OIS), in
combination with WT p53, activated MYC, low
CD8 T cell
+
Notch signaling, active Wnt signaling, activated
RAS, or active mTOR signaling induces a senes-
Macrophage
cence-associated secretory phenotype (SASP)
that leads to the recruitment and activation of
Notchhigh
Non-senescent
malignant cell macrophages, neutrophils, NK cells, and CD8+
Neutrophil
T cells that clear senescent cells and thus limit
Chronic inflammation
& immunosuppresion
tumorigenesis.
(B) Loss or loss-of-function mutations in p53, or
activated RAS, Notch, or mTOR signaling can
lead to an alternative SASP that also attributes to
a chronic inflammatory state that establishes an
immunosuppressive tumor microenvironment.
Immunosuppressive macrophages and neutro-
phils limit NK and CD8+ T cell-mediated anti-tu-
Tumor mor response and thus promote tumorigenesis.
NF-kB and STAT3 signaling in senescent cells is
key in SASP induction.
cells can actively counteract SASP by producing IL-1 receptor
antagonist (Di Mitri et al., 2014). Additionally, senescence pro-
grams in tumor-associated stromal cells also impact tumorigen-
esis through modulation of immune responses. In a carbon
tetrachloride (CCl4)-induced liver fibrosis model, p53 activity in
hepatic stellate cells (HSCs) limits fibrosis and cirrhosis, and
reduced liver tumorigenesis in mice treated with CCl4 and
diethylnitrosamine (DEN) (Lujambio et al., 2013). Here, wild-
type p53 cooperated with NF-kB to induce senescence and
SASP in HSCs, which induced a tumor-inhibiting phenotype in
macrophages. Loss of p53 in stromal HSCs changed their secre-
tome, induced the polarization of macrophages toward a tumor-
promoting phenotype and accelerated inflammation-induced
hepatocellular carcinoma (Lujambio et al., 2013), indicating
that also stromal cell-intrinsic p53 controls tumorigenesis via
modulation of the immune system.
Collectively, depending on the tumor type and oncogenic wir-
ing, the activated SASP-related genes and downstream inflam-
matory profile may differ, resulting in a wide spectrum of immune
responses that range from tumor-promoting chronic inflamma-
tory responses to immune-mediated clearance of cancer cells
(Figure 2). Deeper mechanistic insights into the causal relation-
ship between genetic events in cancer cells and the dynamic
aspects of SASP may open new avenues for therapeutic inter-
vention. Indeed, this is exemplified by a study showing that the
efficacy of docetaxel could be enhanced by pharmacologically
targeting Pten-loss-induced SASP in a transgenic prostate tu-
mor model (Toso et al., 2014). Important to note however, is
that senescent cells are not the only cells actively secreting in-
flammatory mediators in the tumor, and the cytokine milieu
and its net effect on the immune landscape is not only deter-
mined by SASP. Therefore, it is of key importance to delineate
how the tumor-promoting aspects of SASP can be reverted,
while enhancing the tumor-limiting aspects.
Mechanisms of Cancer-Cell-Intrinsic Regulation of
Parameters of the Cancer Immunity Cycle and Immune
Checkpoint Blockade Response
As discussed above, the mutational load of tumors is one of
the determinants linked with responsiveness to immune check-
point inhibition. The expectation is that many other parameters,
Immunity 48, March 20, 2018 409

including the activation of certain oncogenes or inactivation of
TSGs, are associated with therapeutic benefit as well, and that
they may differ per tumor (sub)type. As of yet, preclinical studies
focused on unlocking the relationship between tumor genetics
and response to immunotherapy are still relatively limited, how-
ever, the concept is emerging that genetic events in cancer cells
dictate various aspects of the tumor-immunity cycle (Chen and
Mellman, 2013), such as activation of immunosuppressive
myeloid cells, induction of immune checkpoint molecule expres-
sion, regulation of DC activation and T cell priming, and induction
of tumor resistance to T cell attack.
One such genetic event is mutation in the serine/threonine-
protein kinase ATR. ATR is a DNA damage sensor and is
frequently mutated in melanoma. It has been reported to influ-
ence important parameters of immunotherapy response, such
as intratumoral T cell influx and expression of immune check-
points. Transgenic expression of an ATR LOF mutant in the
Tyr::CreERT2; BrafV600E;PtenF/F model for melanoma diminished
T cell influx in the tumor, while increasing B cells and macro-
phages (Chen et al., 2017). This was associated with an increase
in expression of Arginase 1, CD206, and PD-L1 in the tumor,
suggesting a more T cell suppressed environment. Cyclin-
dependent kinases (CDKs)—essential regulators of the cell
cycle—have also been shown to be involved in immune check-
point regulation. In medulloblastoma (MB) cell line inoculation
models, the anti-tumor function of CD4+ T cells depends on
disruption of CDK5 in MB cells (Dorand et al., 2016). In this
model, CDK5 is required for PD-L1 expression by MB cells, as
CDK5 is a repressor of IRF2 and IRF2BP2, that both regulate
IFN-g-mediated PD-L1 expression (Dorand et al., 2016). Addi-
tionally, it was recently shown that the activating RasG12V muta-
tion can cause stabilization of PD-L1 mRNA via activation of
MEK (Coelho et al., 2017). However, the functional relevance of
these changes for immunotherapy and disease progression in
relation to ATR, CDK5, and RAS remains unaddressed in these
studies.
Another mechanism by which tumor cells may regulate immu-
notherapy response is via establishment of an immunosuppres-
sive microenvironment. Overexpression of PRCKI, a protein
kinase, is frequently observed in a variety of cancer types,
including high-grade serous ovarian carcinoma (Sarkar et al.,
2017). Upon conditional overexpression of PRKCI in the Pax8-
rtta;TetO-Cre;Trp53F/F;PtenF/F mouse model for ovarian cancer,
tumors upregulated TNF-a, as a result of which tumors were
strongly infiltrated by immunosuppressive neutrophils, thus
decreasing CD8+ T cell influx (Sarkar et al., 2017). This TNF-a-
mediated neutrophil recruitment was dependent on PRKCI-
induced YAP1—a key transcriptional regulator and onco-
gene—signaling in cancer cells (Sarkar et al., 2017). Likewise,
by comparing Pb-cre4;PtenF/F with Pb-cre4;PtenF/F;Smad4F/F
prostate cancer mouse models, a strong YAP1-dependent influx
of neutrophils was observed upon cancer cell-intrinsic Smad4
loss (Wang et al., 2016). Here, Smad4 loss caused YAP1-
mediated upregulation of CXCL5 in tumor cells. This in turn re-
cruited CXCR2+ neutrophils, which suppressed the CD8+ T cell
response to the tumor (Wang et al., 2016). These studies show
that Smad4 and PRCKI both function as inducers of immunosup-
pression via cancer cell-intrinsic YAP signaling and that YAP in-
hibitors—which are currently in preclinical development—may
410 Immunity 48, March 20, 2018
Immunity
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prove beneficial to alleviate T cell suppression. Collectively,
these studies show that oncogenic pathway activation can
significantly impact on parameters of the cancer-immunity cycle.
However, the functional consequences of these genetic changes
on immunotherapy response have not been addressed in these
studies. Focal Adhesion Kinase (FAK) activity in cancer cells has
also been identified as an important regulator of immunosup-
pression in the tumor microenvironment, and its impact on
immunotherapy efficacy has been addressed experimentally.
FAK amplification was observed in the p48-Cre;KrasLSL-G12D;
Trp53F/+ model for PDAC, and therapeutic targeting of FAK
improved survival by alleviating the immunosuppressive micro-
environment, mainly by reducing macrophages, monocytes,
and neutrophils in the tumor (Jiang et al., 2016). This held true
for cancer-cell-specific ablation of FAK, indicating that immune
cell changes occur via FAK targeting in cancer cells. Importantly,
inhibition of FAK synergized with anti-CTLA-4/anti-PD-1 combi-
nation immunotherapy (Jiang et al., 2016), indicating that inter-
ference with this cancer cell-intrinsic signaling pathway renders
tumors sensitive to immunotherapy.
DC activation and T cell priming can also be influenced by
cancer cell-intrinsic signaling pathways. Using the BrafV600E;
Pten–/–;CAT-STA mouse model for melanoma, which expresses
constitutively active b-catenin, it was revealed that b-catenin
signaling prevented expression of CCL4 by cancer cells, result-
ing in suppression of recruitment of CD103+ DCs and impaired
priming and intratumoral accumulation of T cells (Spranger
et al., 2015). As a consequence, b-catenin-active tumors failed
to respond to anti-CTLA-4/anti-PD-1 treatment. In line with these
data, active WNT/b-catenin signaling in human metastatic mela-
nomas correlated with absence of a T cell gene expression
signature (Spranger et al., 2015). This study highlights the impor-
tance of cancer cell-intrinsic WNT/b-catenin signaling in immune
evasion of tumors, and suggests that targeting the WNT pathway
may improve the therapeutic benefit of immune checkpoint inhi-
bition in tumors with active b-catenin signaling.
Some oncogenes and TSGs have been demonstrated to regu-
late immune checkpoint molecule expression in a cell-autono-
mous fashion, and thus influence response to immunotherapy.
In EGFR-driven lung cancer mouse models, EGFR mutation
caused rapid induction of an immunosuppressive tumor micro-
environment (Akbay et al., 2013). The EGFR mutant lung tumors
displayed increased expression of immune checkpoint mole-
cules such as PD-1 and PD-L1, which led to an increased sensi-
tivity to anti-PD-1 monotherapy in these tumor-bearing mice. In
line with these pre-clinical findings, EGFR pathway activating
mutations in human lung tumors, and not the other prevalent
driver mutation KRASG12V, correlated with PD-L1 expression
(Akbay et al., 2013). Intriguingly, another study reported KRAS
mutant lung tumors in patients treated with anti-PD-1 to have
higher PD-L1 levels relative to EGFR mutated tumors (Garon
et al., 2015), potentially mediated by KRAS-induced stabilization
of PD-L1 (Coelho et al., 2017). The different levels of PD-L1 regu-
lation by mutated oncogenes and the underlying mechanisms
will therefore be an important topic of future research.
Similarly, PTEN status is implicated in immunotherapy
response due to its ability to render cancer cells resistant to
T cell attack. In a cohort of melanoma patients, PTEN loss corre-
lated with low TIL influx and poor response to anti-PD-1 therapy
Immunity
Review
A B
C tumor. Combined with anti-PD-L1 treatment, this
PTEN null melanomas, the resulting activated AKT signaling can be reduced by PI3Kb inhibitors, which in combination with anti-PD-1 limits tumor growth (Peng
V600E
et al., 2016). Combining MEK and BRAF inhibitors in BRAF
(E) In prostate tumors with loss of SMAD4, YAP1-mediated immunosuppressive neutrophil recruitment can be counteracted by YAP1 inhibitors or anti-CXCR2
treatment (Wang et al., 2016).
(Peng et al., 2016). Using xenograft mouse models for mela-
noma, it was shown that PTEN loss in cancer cells reduced
T cell influx, and resulted in reduced autophagy, leading to resis-
tance to T cell-mediated killing (Peng et al., 2016). Treating PTEN
null tumors with a PI3Kb inhibitor, thus reducing the dysregu-
lated AKT activity in these tumors, improved response to anti-
PD-1 therapy, highlighting a potential therapeutic approach for
PTEN null melanoma in controlling resistance to anti-PD-1
therapy.
Altogether, these studies show that aberrant signaling path-
ways in cancer cells can impact the anti-cancer immune
response and the response to immune checkpoint inhibition
(Figure 3). One aspect that needs to be taken into account
when using GEMMs to model human cancers with high muta-
tional load, is that the mutational load in transgenic mice may
not correspond to that of the human tumors, due to the strong
driver mutations engineered in these mice. This could be over-
come by for example exposing early melanoma lesions to UV
irradiation, or early lung lesions to carcinogens. The drawback
however, is that this may not result in clonal antigens and the
mutational spectrum may be highly variable from one mouse to
the next. Alternatively, transgenic models that are prone to
generate high mutational load tumors can be used, such as
Figure 3. How to Exploit the Genetic
Makeup of Individual Tumors to Allow for
Patient-Specific Immune-Based
Therapeutic Interventions
Maximizing therapeutic efficacy by rational se-
lection of targeted drugs and immunomodulatory
compounds based on the genetics of the tumor.
Examples depicted here are mainly based on pre-
clinical intervention studies, with therapeutic mo-
dalities highlighted in red. For every example a
mouse or human symbol is used to depict what is
based on clinical or pre-clinical evidence.
(A) In breast cancer, CDK4/6 inhibition increases
D
antigen presentation, interferon signaling, and
CD8+ T cell levels, while decreasing Tregs in the
leads to a marked tumor regression (Goel et al.,
2017).
(B) In EGFR mutant lung cancer, PD-L1 has been
described to be upregulated, increasing the
sensitivity to anti-PD-L1 therapy (Akbay et al.,
2013). KRAS mutation in lung cancer can also
drive PD-L1 expression, to a higher extent than
EGFR mutation (Garon et al., 2015). In MYC-driven
lung tumors, combined inhibitors against HDAC
E and DNMT both target MYC and CD8+ T cells, thus
limiting tumor growth (Topper et al., 2017).
(C) Pancreatic tumors with FAK amplification
show an accumulation of immunosuppressive
cells in the tumor. FAK1/2 inhibitors alleviate this,
and combined with anti-PD-1 and anti-CTLA-4
treatment limit tumor progression (Jiang et al.,
2016). Pancreatic tumors with p53 loss or muta-
tion establish an immunosuppressive microenvi-
ronment by JAK-STAT signaling. Targeting JAK2
in combination with gemcitabine reduces tumor
burden (Wörmann et al., 2016).
(D) In melanoma, ATR loss-of-function mutation
increases PD-L1 and thereby potentially sensi-
tizes these tumors to anti-PD-L1 treatment. In
mutant melanoma also synergize with anti-PD-1 treatment (Hu-Lieskovan et al., 2015).
those with mutations in DNA repair machinery, or mutations
can be engineered in a tissue-specific manner. This would allow
for physiological modeling and therefore correct assessment of
pre-clinical immunotherapeutic strategies in an immunocompe-
tent setting.
Targeting Genetic Pathways to Unleash Anti-Tumor
Immunity
One major theme that emerges from the aforementioned studies
is that many targeted therapies, specific for hyperactive
signaling pathways, are likely to also exert a major impact on
the immune contexture of tumors. Most targeted drugs initially
induce very strong anti-cancer effects in patients, however, the
rate of durable clinical responses is disappointingly low (Groe-
nendijk and Bernards, 2014). Given the previously unrecognized
impact of these targeted drugs on the immune landscape of tu-
mors, the question arises whether we can rationally induce a
favorable immune environment in tumors or even sensitize tu-
mors to immunomodulatory drugs by selective usage of targeted
therapy. In this regard, we can learn from the growing number of
pre-clinical studies that have addressed the impact of targeted
drugs on the immune microenvironment of tumors and their
response to immunotherapy. For example, as described above,
Immunity 48, March 20, 2018 411

BRAF mutant thyroid tumors are characterized by infiltration of
immunosuppressive cells (Charoentong et al., 2017), raising
the question of whether inhibition of mutant BRAF in thyroid can-
cer would induce a more favorable immune contexture. Indeed,
combined targeting of BRAFV600E and SRC increased influx of
CD8+ T cells, B cells, and macrophages and reduced tumor
growth in an orthotopic inoculation model for anaplastic thyroid
cancer (Vanden Borre et al., 2014). Also in patients with
BRAFV600E mutated metastatic melanoma, BRAF inhibition with
vemurafenib enhanced melanoma antigen presentation by can-
cer cells, increased cytotoxic T cell influx, and decreased immu-
nosuppression (Frederick et al., 2013). This is in line with findings
in BRAFV600E melanoma mouse models in which BRAF inhibition
improved adoptive T cell therapy (Koya et al., 2012) and BRAF
inhibition combined with MEK inhibition synergized with anti-
PD-1 treatment (Hu-Lieskovan et al., 2015). These studies
indicate that therapeutic targeting of cancer cell-intrinsic
oncogenic driver mutations can be exploited to induce a favor-
able immune environment and thus sensitize tumors to cancer
immunotherapy.
Other targeted therapies have also been reported to exert
strong effects on the cancer-immune cell crosstalk. For
example, CDK4/6 inhibitors were originally designed to selec-
tively inhibit cell-cycle progression, but emerging experimental
evidence reveals that part of the therapeutic benefit of these in-
hibitors lies in their anti-tumor immunity promoting capacity. In
the MMTV-rtTA/tetO-HER2 mouse model for breast cancer,
treatment with the CDK4/6 inhibitor abemaciclib leads to tumor
regression by inducing anti-tumor immunity (Goel et al., 2017).
In vitro studies revealed that CDK4/6 inhibition increased antigen
presentation and production of type III interferons by cancer
cells, which induced CD8+ T cell proliferation and activation
(Goel et al., 2017). Simultaneously, CDK4/6 inhibition reduced
systemic and intra-tumoral regulatory T cell numbers, which
occurred independent of the presence of a tumor. Both the effect
of the CDK4/6 inhibitor on antigen presentation by cancer cells
and the impact on regulatory T cells was dependent on inhibition
of the RB-E2F-DNMT1 axis (Goel et al., 2017). Importantly, by
modulating the immune microenvironment, anti-CDK4/6 treat-
ment improved response to anti-PDL1 in MMTV-rtTA/tetO-
HER2 mice (Goel et al., 2017). Also, in an in vitro small molecule
screen, CDK4/6 inhibitors were identified to directly enhance
T cell activity. Mechanistically, CDK4/6 inhibition resulted in
de-repression of NFAT activity in T cells, resulting in increased
T cell accumulation in lung tumors of KrasLSL-G12D;Trp53F/F
mice, which synergized with immune checkpoint inhibition
(Deng et al., 2018). These two studies illustrate that CDK4/6
inhibitors, which were originally developed to induce cell-cycle
arrest in cancer cells, work in part by counteracting tumor im-
mune evasion. This is a result of combined targeting of cancer
cell-intrinsic pathways, changing parameters of the cancer-im-
munity cycle, and direct targeting of T cells.
Targeted therapies have also been reported to affect the abun-
dance and function of myeloid cells in tumor-bearing hosts,
since the signaling pathways targeted by these drugs also play
functional roles in the immune system (Muñoz-Fontela et al.,
2016). For example, neutrophils in the Hgf-Cdk4R24C model for
melanoma and cell line inoculation models impair the anti-tumor
CD8+ T cell response (Glodde et al., 2017). In this study, cMET
412 Immunity 48, March 20, 2018
Immunity
Review
inhibition enhanced the efficacy of adoptive cell transfer and im-
mune checkpoint therapies by direct targeting of immunosup-
pressive neutrophils that express the cMET receptor (Glodde
et al., 2017). However, targeting cMET-expressing neutrophils
in another study promotes tumor progression (Finisguerra
et al., 2015), highlighting the complex model-dependent and
dual role of neutrophils in cancer biology (Coffelt et al., 2016).
Likewise, it has been reported that the depletion of immunosup-
pressive CD11b+Gr1+ cells as a bystander effect of other
targeted therapies, for example by ITK/BTK-inhibitor ibrutinib,
benefits the response to immunotherapies in cell line inoculation
models for breast cancer and melanoma (Sagiv-Barfi et al., 2015;
Stiff et al., 2016). Ibrutinib can also reprogram macrophages,
relieve immunosuppression, and facilitate CD8+ cytotoxicity in
PDAC-bearing mice (Gunderson et al., 2016). These studies
highlight that targeted drugs can impact the immune contexture
of tumors via their working mechanism on cancer cells, which
indirectly changes the immune landscape, and via their direct
effect on immune cells. Insights into the complexity of the com-
bined effect of these targeted drugs on the cancer cells and tu-
mor microenvironment will help us to maximize the therapeutic
benefit of targeted drugs in combination with immunomodula-
tory strategies (Figure 3).
Conclusions and Future Directions
From the studies discussed in this review it has become clear
that activation of oncogenes or loss of TSGs not only exert an
intrinsic influence on the fate of cancer cells, but can have pro-
found effects on tumor-host interactions. Commonly mutated
genes that lie at the basis of tumorigenesis can actively partici-
pate in recruitment, activation, or dampening of the immune sys-
tem. This could in part explain the heterogeneity between and
within tumor types in immune infiltration and activation. From a
clinical perspective, these insights will help identify patients
that would or would not benefit from immunomodulation. More-
over, identifying the mechanisms underlying the causal relation-
ship between the genetic makeup of tumors and their immune
landscape may identify novel targets for anti-cancer immuno-
modulatory therapies. The studies presented here likely only
reveal the tip of the iceberg. Most studies focus on one particular
oncogene or TSG, and the majority of research is concentrated
on the primary tumor. This leaves the effect on the systemic im-
mune milieu and metastasis largely unaddressed. With increas-
ingly sophisticated methodologies to generate mouse models
that closely mimic the genetics and biology of human cancer
and approaches to analyze tumors in depth, it will be possible
to screen for a multitude of genetic and epigenetic alterations
and their effect on the immune system. In vivo genetic manipula-
tion will be key to delineate the spatiotemporal regulation of the
tumor immune landscape, both in the primary as well as the met-
astatic lesion. This knowledge will help maximize the potential of
immunomodulatory therapeutics for cancer patients and provide
rationale for personalized combination therapies based on the
genetic profile of tumors.
ACKNOWLEDGMENTS
We apologize to those researchers whose original work could not be cited due
to space restrictions. We would like to thank Hannah Garner for insightful input
Immunity
Review
during the writing process. Research in the De Visser laboratory is funded by
European Research Council Consolidator award (InflaMet 615300), the Dutch
Cancer Society (KWF10083; KWF10623), and the Beug Foundation for Metas-
tasis Research. K.E.d.V. is an EMBO Young Investigator.
REFERENCES
Adams, J.M., Harris, A.W., Pinkert, C.A., Corcoran, L.M., Alexander, W.S.,
Cory, S., Palmiter, R.D., and Brinster, R.L. (1985). The c-myc oncogene driven
by immunoglobulin enhancers induces lymphoid malignancy in transgenic
mice. Nature 318, 533–538.
Akbay, E.A., Koyama, S., Carretero, J., Altabef, A., Tchaicha, J.H., Christen-
sen, C.L., Mikse, O.R., Cherniack, A.D., Beauchamp, E.M., Pugh, T.J., et al.
(2013). Activation of the PD-1 pathway contributes to immune escape in
EGFR-driven lung tumors. Cancer Discov. 3, 1355–1363.
Ancrile, B., Lim, K.H., and Counter, C.M. (2007). Oncogenic Ras-induced
secretion of IL6 is required for tumorigenesis. Genes Dev. 21, 1714–1719.
Bailey, P., Chang, D.K., Nones, K., Johns, A.L., Patch, A.M., Gingras, M.C.,
Miller, D.K., Christ, A.N., Bruxner, T.J., Quinn, M.C., et al.; Australian Pancre-
atic Cancer Genome Initiative (2016). Genomic analyses identify molecular
subtypes of pancreatic cancer. Nature 531, 47–52.
Balkwill, F., and Mantovani, A. (2001). Inflammation and cancer: back to
Virchow? Lancet 357, 539–545.
Balli, D., Rech, A.J., Stanger, B.Z., and Vonderheide, R.H. (2017). Immune
Cytolytic Activity Stratifies Molecular Subsets of Human Pancreatic Cancer.
Clin. Cancer Res. 23, 3129–3138.
Becht, E., de Reyniès, A., Giraldo, N.A., Pilati, C., Buttard, B., Lacroix, L.,
Selves, J., Sautès-Fridman, C., Laurent-Puig, P., and Fridman, W.H. (2016).
Immune and Stromal Classification of Colorectal Cancer Is Associated with
Molecular Subtypes and Relevant for Precision Immunotherapy. Clin. Cancer
Res. 22, 4057–4066.
Beroukhim, R., Mermel, C.H., Porter, D., Wei, G., Raychaudhuri, S., Donovan,
J., Barretina, J., Boehm, J.S., Dobson, J., Urashima, M., et al. (2010). The land-
scape of somatic copy-number alteration across human cancers. Nature 463,
899–905.
Bezzi, M., Seitzer, N., Ishikawa, T., Reschke, M., Chen, M., Wang, G., Mitchell,
C., Ng, C., Katon, J., Lunardi, A., et al. (2018). Diverse genetic-driven immune
landscapes dictate tumor progression through distinct mechanisms. Nat.
Med. 24, 165–175.
Blaisdell, A., Crequer, A., Columbus, D., Daikoku, T., Mittal, K., Dey, S.K., and
Erlebacher, A. (2015). Neutrophils Oppose Uterine Epithelial Carcinogenesis
via Debridement of Hypoxic Tumor Cells. Cancer Cell 28, 785–799.
Boveri, T. (1914). Zur Frage der Entstehung Maligner Tumoren. Gustav Fischer
1914, 1–64.
Brandetti, E., Veneziani, I., Melaiu, O., Pezzolo, A., Castellano, A., Boldrini, R.,
Ferretti, E., Fruci, D., Moretta, L., Pistoia, V., et al. (2017). MYCN is an immu-
nosuppressive oncogene dampening the expression of ligands for NK-cell-
activating receptors in human high-risk neuroblastoma. OncoImmunology 6,
e1316439.
Busch, S.E., Hanke, M.L., Kargl, J., Metz, H.E., MacPherson, D., and
Houghton, A.M. (2016). Lung Cancer Subtypes Generate Unique Immune
Responses. J. Immunol. 197, 4493–4503.
Casey, S.C., Tong, L., Li, Y., Do, R., Walz, S., Fitzgerald, K.N., Gouw, A.M.,
€tgemann, I., Eilers, M., and Felsher, D.W. (2016). MYC regulates
Baylot, V., Gu
the antitumor immune response through CD47 and PD-L1. Science 352,
227–231.
Cha, Y.J., Kim, H.R., Lee, C.Y., Cho, B.C., and Shim, H.S. (2016). Clinicopath-
ological and prognostic significance of programmed cell death ligand-1
expression in lung adenocarcinoma and its relationship with p53 status.
Lung Cancer 97, 73–80.
Charoentong, P., Finotello, F., Angelova, M., Mayer, C., Efremova, M., Rieder, D.,
Hackl, H., and Trajanoski, Z. (2017). Pan-cancer Immunogenomic Analyses
Reveal Genotype-Immunophenotype Relationships and Predictors of Response
to Checkpoint Blockade. Cell Rep. 18, 248–262.
Chen, D.S., and Mellman, I. (2013). Oncology meets immunology: the cancer-
immunity cycle. Immunity 39, 1–10.
Chen, Z., Chen, X., Zhou, E., Chen, G., Qian, K., Wu, X., Miao, X., and Tang, Z.
(2014). Intratumoral CD8+ cytotoxic lymphocyte is a favorable prognostic
marker in node-negative breast cancer. PLoS ONE 9, e95475.
Chen, C.F., Ruiz-Vega, R., Vasudeva, P., Espitia, F., Krasieva, T.B., de Fer-
audy, S., Tromberg, B.J., Huang, S., Garner, C.P., Wu, J., et al. (2017). ATR
Mutations Promote the Growth of Melanoma Tumors by Modulating the
Immune Microenvironment. Cell Rep. 18, 2331–2342.
Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J.E., Pre-
msrirut, P., Luo, W., Chicas, A., Lee, C.S., et al. (2011). Control of the senes-
cence-associated secretory phenotype by NF-kB promotes senescence and
enhances chemosensitivity. Genes Dev. 25, 2125–2136.
Coelho, M.A., de Carné Trécesson, S., Rana, S., Zecchin, D., Moore, C., Mo-
lina-Arcas, M., East, P., Spencer-Dene, B., Nye, E., Barnouin, K., et al. (2017).
Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing
PD-L1 mRNA. Immunity 47, 1083–1099.e6.
Coffelt, S.B., Wellenstein, M.D., and de Visser, K.E. (2016). Neutrophils in can-
cer: neutral no more. Nat. Rev. Cancer 16, 431–446.
Coley, W.B. (1893). The treatment of malignant tumors by repeated inocula-
tions of erysipelas: with a report of ten original cases. Am. J. Med. Sci. 105,
487–511.
Cooks, T., Pateras, I.S., Tarcic, O., Solomon, H., Schetter, A.J., Wilder, S., Loz-
ano, G., Pikarsky, E., Forshew, T., Rosenfeld, N., et al. (2013). Mutant p53
prolongs NF-kB activation and promotes chronic inflammation and inflamma-
tion-associated colorectal cancer. Cancer Cell 23, 634–646.
Cooks, T., Harris, C.C., and Oren, M. (2014). Caught in the cross fire: p53 in
inflammation. Carcinogenesis 35, 1680–1690.
Debebe, A., Medina, V., Chen, C.Y., Mahajan, I.M., Jia, C., Fu, D., He, L., Zeng,
N., Stiles, B.W., Chen, C.L., et al. (2017). Wnt/b-catenin activation and macro-
phage induction during liver cancer development following steatosis. Onco-
gene 36, 6020–6029.
Decker, T., Fischer, G., Bu€cke, W., Bu €cke, P., Stotz, F., Gru€neberger, A.,
Gropp-Meier, M., Wiedemann, G., Pfeiffer, C., Peschel, C., and Götze, K.
(2012). Increased number of regulatory T cells (T-regs) in the peripheral blood
of patients with Her-2/neu-positive early breast cancer. J. Cancer Res. Clin.
Oncol. 138, 1945–1950.
Deng, J., Wang, E.S., Jenkins, R.W., Li, S., Dries, R., Yates, K., Chhabra, S.,
Huang, W., Liu, H., Aref, A.R., et al. (2018). CDK4/6 Inhibition Augments Anti-
tumor Immunity by Enhancing T-cell Activation. Cancer Discov. 8, 216–233.
Di Mitri, D., Toso, A., Chen, J.J., Sarti, M., Pinton, S., Jost, T.R., D’Antuono, R.,
Montani, E., Garcia-Escudero, R., Guccini, I., et al. (2014). Tumour-infiltrating
Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134–137.
Diakos, C.I., Charles, K.A., McMillan, D.C., and Clarke, S.J. (2014). Cancer-
related inflammation and treatment effectiveness. Lancet Oncol. 15,
e493–e503.
Donehower, L.A., Harvey, M., Slagle, B.L., McArthur, M.J., Montgomery, C.A.,
Jr., Butel, J.S., and Bradley, A. (1992). Mice deficient for p53 are developmen-
tally normal but susceptible to spontaneous tumours. Nature 356, 215–221.
Dorand, R.D., Nthale, J., Myers, J.T., Barkauskas, D.S., Avril, S., Chirieleison,
S.M., Pareek, T.K., Abbott, D.W., Stearns, D.S., Letterio, J.J., et al. (2016).
Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor
immunity. Science 353, 399–403.
Doucette, T., Rao, G., Rao, A., Shen, L., Aldape, K., Wei, J., Dziurzynski, K.,
Gilbert, M., and Heimberger, A.B. (2013). Immune heterogeneity of glioblas-
toma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol.
Res. 1, 112–122.
Duesberg, P.H., and Vogt, P.K. (1970). Differences between the ribonucleic
acids of transforming and nontransforming avian tumor viruses. Proc. Natl.
Acad. Sci. USA 67, 1673–1680.
Finisguerra, V., Di Conza, G., Di Matteo, M., Serneels, J., Costa, S., Thompson,
A.A., Wauters, E., Walmsley, S., Prenen, H., Granot, Z., et al. (2015). MET is
required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353.
Immunity 48, March 20, 2018 413

Fisher, G.H., Wellen, S.L., Klimstra, D., Lenczowski, J.M., Tichelaar, J.W.,
Lizak, M.J., Whitsett, J.A., Koretsky, A., and Varmus, H.E. (2001). Induction
and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras
transgene in the presence and absence of tumor suppressor genes. Genes
Dev. 15, 3249–3262.
Frederick, D.T., Piris, A., Cogdill, A.P., Cooper, Z.A., Lezcano, C., Ferrone,
C.R., Mitra, D., Boni, A., Newton, L.P., Liu, C., et al. (2013). BRAF inhibition
is associated with enhanced melanoma antigen expression and a more favor-
able tumor microenvironment in patients with metastatic melanoma. Clin.
Cancer Res. 19, 1225–1231.
Garon, E.B., Rizvi, N.A., Hui, R., Leighl, N., Balmanoukian, A.S., Eder, J.P., Pat-
naik, A., Aggarwal, C., Gubens, M., Horn, L., et al.; KEYNOTE-001 Investiga-
tors (2015). Pembrolizumab for the treatment of non-small-cell lung cancer.
N. Engl. J. Med. 372, 2018–2028.
Gentles, A.J., Newman, A.M., Liu, C.L., Bratman, S.V., Feng, W., Kim, D., Nair,
V.S., Xu, Y., Khuong, A., Hoang, C.D., et al. (2015). The prognostic landscape
of genes and infiltrating immune cells across human cancers. Nat. Med. 21,
938–945.
Glodde, N., Bald, T., van den Boorn-Konijnenberg, D., Nakamura, K.,
O’Donnell, J.S., Szczepanski, S., Brandes, M., Eickhoff, S., Das, I., Shridhar,
N., et al. (2017). Reactive Neutrophil Responses Dependent on the Receptor
Tyrosine Kinase c-MET Limit Cancer Immunotherapy. Immunity 47, 789–
802 e789.
Goel, S., DeCristo, M.J., Watt, A.C., BrinJones, H., Sceneay, J., Li, B.B., Khan,
N., Ubellacker, J.M., Xie, S., Metzger-Filho, O., et al. (2017). CDK4/6 inhibition
triggers anti-tumour immunity. Nature 548, 471–475.
Groenendijk, F.H., and Bernards, R. (2014). Drug resistance to targeted thera-
pies: déjà vu all over again. Mol. Oncol. 8, 1067–1083.
Gunderson, A.J., Kaneda, M.M., Tsujikawa, T., Nguyen, A.V., Affara, N.I., Ruf-
fell, B., Gorjestani, S., Liudahl, S.M., Truitt, M., Olson, P., et al. (2016). Bruton
Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.
Cancer Discov. 6, 270–285.
Hanahan, D., Wagner, E.F., and Palmiter, R.D. (2007). The origins of oncomice:
a history of the first transgenic mice genetically engineered to develop cancer.
Genes Dev. 21, 2258–2270.
Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C.J.,
Raguz, S., Acosta, J.C., Innes, A.J., Banito, A., et al. (2015). mTOR regulates
MAPKAPK2 translation to control the senescence-associated secretory
phenotype. Nat. Cell Biol. 17, 1205–1217.
Hoare, M., Ito, Y., Kang, T.W., Weekes, M.P., Matheson, N.J., Patten, D.A.,
Shetty, S., Parry, A.J., Menon, S., Salama, R., et al. (2016). NOTCH1 mediates
a switch between two distinct secretomes during senescence. Nat. Cell Biol.
18, 979–992.
Hu-Lieskovan, S., Mok, S., Homet Moreno, B., Tsoi, J., Robert, L., Goedert, L.,
Pinheiro, E.M., Koya, R.C., Graeber, T.G., Comin-Anduix, B., and Ribas, A.
(2015). Improved antitumor activity of immunotherapy with BRAF and MEK in-
hibitors in BRAF(V600E) melanoma. Sci. Transl. Med. 7, 279ra41.
Hugo, W., Zaretsky, J.M., Sun, L., Song, C., Moreno, B.H., Hu-Lieskovan, S.,
Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., et al. (2016). Genomic
and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic
Melanoma. Cell 165, 35–44.
Huijbers, I.J. (2017). Generating Genetically Modified Mice: A Decision Guide.
Methods Mol. Biol. 1642, 1–19.
Jain, M., Arvanitis, C., Chu, K., Dewey, W., Leonhardt, E., Trinh, M., Sundberg,
C.D., Bishop, J.M., and Felsher, D.W. (2002). Sustained loss of a neoplastic
phenotype by brief inactivation of MYC. Science 297, 102–104.
Ji, H., Houghton, A.M., Mariani, T.J., Perera, S., Kim, C.B., Padera, R., Tonon,
G., McNamara, K., Marconcini, L.A., Hezel, A., et al. (2006). K-ras activation
generates an inflammatory response in lung tumors. Oncogene 25,
2105–2112.
Jiang, D., Gao, Z., Cai, Z., Wang, M., and He, J. (2015). Clinicopathological and
prognostic significance of FOXP3+ tumor infiltrating lymphocytes in patients
with breast cancer: a meta-analysis. BMC Cancer 15, 727.
Jiang, H., Hegde, S., Knolhoff, B.L., Zhu, Y., Herndon, J.M., Meyer, M.A.,
Nywening, T.M., Hawkins, W.G., Shapiro, I.M., Weaver, D.T., et al. (2016). Tar-
414 Immunity 48, March 20, 2018
Immunity
Review
geting focal adhesion kinase renders pancreatic cancers responsive to check-
point immunotherapy. Nat. Med. 22, 851–860.
Kang, T.W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D.,
Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011). Senes-
cence surveillance of pre-malignant hepatocytes limits liver cancer develop-
ment. Nature 479, 547–551.
Kastenhuber, E.R., and Lowe, S.W. (2017). Putting p53 in Context. Cell 170,
1062–1078.
Katlinski, K.V., Gui, J., Katlinskaya, Y.V., Ortiz, A., Chakraborty, R., Bhatta-
charya, S., Carbone, C.J., Beiting, D.P., Girondo, M.A., Peck, A.R., et al.
(2017). Inactivation of Interferon Receptor Promotes the Establishment of Im-
mune Privileged Tumor Microenvironment. Cancer Cell 31, 194–207.
Keck, M.K., Zuo, Z., Khattri, A., Stricker, T.P., Brown, C.D., Imanguli, M.,
€gelmann, J., et al. (2015). Integrative anal-
Rieke, D., Endhardt, K., Fang, P., Bra
ysis of head and neck cancer identifies two biologically distinct HPV and three
non-HPV subtypes. Clin. Cancer Res. 21, 870–881.
Kersten, K., de Visser, K.E., van Miltenburg, M.H., and Jonkers, J. (2017).
Genetically engineered mouse models in oncology research and cancer med-
icine. EMBO Mol. Med. 9, 137–153.
Knudson, A.G., Jr. (1971). Mutation and cancer: statistical study of retinoblas-
toma. Proc. Natl. Acad. Sci. USA 68, 820–823.
Kobielak, A., and Fuchs, E. (2006). Links between alpha-catenin, NF-kappaB,
and squamous cell carcinoma in skin. Proc. Natl. Acad. Sci. USA 103,
2322–2327.
Kortlever, R.M., Sodir, N.M., Wilson, C.H., Burkhart, D.L., Pellegrinet, L.,
Brown Swigart, L., Littlewood, T.D., and Evan, G.I. (2017). Myc Cooperates
with Ras by Programming Inflammation and Immune Suppression. Cell 171,
1301–1315.e14.
Koya, R.C., Mok, S., Otte, N., Blacketor, K.J., Comin-Anduix, B., Tumeh, P.C.,
Minasyan, A., Graham, N.A., Graeber, T.G., Chodon, T., and Ribas, A. (2012).
BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell
immunotherapy. Cancer Res. 72, 3928–3937.
Koyama, S., Akbay, E.A., Li, Y.Y., Aref, A.R., Skoulidis, F., Herter-Sprie, G.S.,
Buczkowski, K.A., Liu, Y., Awad, M.M., Denning, W.L., et al. (2016). STK11/
LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory
Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvi-
ronment. Cancer Res. 76, 999–1008.
Laberge, R.M., Sun, Y., Orjalo, A.V., Patil, C.K., Freund, A., Zhou, L., Curran,
S.C., Davalos, A.R., Wilson-Edell, K.A., Liu, S., et al. (2015). MTOR regulates
the pro-tumorigenic senescence-associated secretory phenotype by promot-
ing IL1A translation. Nat. Cell Biol. 17, 1049–1061.
Layer, J.P., Kronmu €ller, M.T., Quast, T., van den Boorn-Konijnenberg, D., Ef-
fern, M., Hinze, D., Althoff, K., Schramm, A., Westermann, F., Peifer, M.,
et al. (2017). Amplification of N-Myc is associated with a T-cell-poor microen-
vironment in metastatic neuroblastoma restraining interferon pathway activity
and chemokine expression. OncoImmunology 6, e1320626.
Le, D.T., Uram, J.N., Wang, H., Bartlett, B.R., Kemberling, H., Eyring, A.D.,
Skora, A.D., Luber, B.S., Azad, N.S., Laheru, D., et al. (2015). PD-1 Blockade
in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 372, 2509–2520.
Lennerz, V., Fatho, M., Gentilini, C., Frye, R.A., Lifke, A., Ferel, D., Wölfel, C.,
Huber, C., and Wölfel, T. (2005). The response of autologous T cells to a human
melanoma is dominated by mutated neoantigens. Proc. Natl. Acad. Sci. USA
102, 16013–16018.
Lesina, M., Wörmann, S.M., Morton, J., Diakopoulos, K.N., Korneeva, O.,
Wimmer, M., Einwa €chter, H., Sperveslage, J., Demir, I.E., Kehl, T., et al.
(2016). RelA regulates CXCL1/CXCR2-dependent oncogene-induced senes-
cence in murine Kras-driven pancreatic carcinogenesis. J. Clin. Invest. 126,
2919–2932.
Linnemann, C., van Buuren, M.M., Bies, L., Verdegaal, E.M., Schotte, R., Calis,
J.J., Behjati, S., Velds, A., Hilkmann, H., Atmioui, D.E., et al. (2015). High-
throughput epitope discovery reveals frequent recognition of neo-antigens
by CD4+ T cells in human melanoma. Nat. Med. 21, 81–85.
Liu, F., Lang, R., Zhao, J., Zhang, X., Pringle, G.A., Fan, Y., Yin, D., Gu, F., Yao,
Z., and Fu, L. (2011). CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infil-
tration in relation to breast cancer survival and molecular subtypes. Breast
Cancer Res. Treat. 130, 645–655.
Immunity
Review
Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D.F., Bolden,
J.E., Zhao, Z., Thapar, V., Joyce, J.A., Krizhanovsky, V., and Lowe, S.W.
(2013). Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460.
Medrek, C., Pontén, F., Jirström, K., and Leandersson, K. (2012). The presence
of tumor associated macrophages in tumor stroma as a prognostic marker for
breast cancer patients. BMC Cancer 12, 306.
Meylan, E., Dooley, A.L., Feldser, D.M., Shen, L., Turk, E., Ouyang, C., and
Jacks, T. (2009). Requirement for NF-kappaB signalling in a mouse model of
lung adenocarcinoma. Nature 462, 104–107.
Moody, S.E., Sarkisian, C.J., Hahn, K.T., Gunther, E.J., Pickup, S., Dugan,
K.D., Innocent, N., Cardiff, R.D., Schnall, M.D., and Chodosh, L.A. (2002). Con-
ditional activation of Neu in the mammary epithelium of transgenic mice results
in reversible pulmonary metastasis. Cancer Cell 2, 451–461.
Muller, P.A., and Vousden, K.H. (2014). Mutant p53 in cancer: new functions
and therapeutic opportunities. Cancer Cell 25, 304–317.
Muñoz-Espı́n, D., and Serrano, M. (2014). Cellular senescence: from physi-
ology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496.
Muñoz-Fontela, C., Mandinova, A., Aaronson, S.A., and Lee, S.W. (2016).
Emerging roles of p53 and other tumour-suppressor genes in immune regula-
tion. Nat. Rev. Immunol. 16, 741–750.
Ock, C.Y., Hwang, J.E., Keam, B., Kim, S.B., Shim, J.J., Jang, H.J., Park, S.,
Sohn, B.H., Cha, M., Ajani, J.A., et al. (2017). Genomic landscape associated
with potential response to anti-CTLA-4 treatment in cancers. Nat. Commun.
8, 1050.
Parker, J.S., Mullins, M., Cheang, M.C., Leung, S., Voduc, D., Vickery, T.,
Davies, S., Fauron, C., He, X., Hu, Z., et al. (2009). Supervised risk predictor
of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160–1167.
Peng, W., Chen, J.Q., Liu, C., Malu, S., Creasy, C., Tetzlaff, M.T., Xu, C.,
McKenzie, J.A., Zhang, C., Liang, X., et al. (2016). Loss of PTEN Promotes
Resistance to T Cell-Mediated Immunotherapy. Cancer Discov. 6, 202–216.
Pérez-Mancera, P.A., Young, A.R., and Narita, M. (2014). Inside and out: the
activities of senescence in cancer. Nat. Rev. Cancer 14, 547–558.
Pribluda, A., Elyada, E., Wiener, Z., Hamza, H., Goldstein, R.E., Biton, M., Bur-
stain, I., Morgenstern, Y., Brachya, G., Billauer, H., et al. (2013). A senescence-
inflammatory switch from cancer-inhibitory to cancer-promoting mechanism.
Cancer Cell 24, 242–256.
Pylayeva-Gupta, Y., Lee, K.E., Hajdu, C.H., Miller, G., and Bar-Sagi, D. (2012).
Oncogenic Kras-induced GM-CSF production promotes the development of
pancreatic neoplasia. Cancer Cell 21, 836–847.
Quigley, D., Silwal-Pandit, L., Dannenfelser, R., Langerød, A., Vollan, H.K.,
Vaske, C., Siegel, J.U., Troyanskaya, O., Chin, S.F., Caldas, C., et al. (2015).
Lymphocyte Invasion in IC10/Basal-Like Breast Tumors Is Associated with
Wild-Type TP53. Mol. Cancer Res. 13, 493–501.
Rizvi, N.A., Hellmann, M.D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J.J.,
Lee, W., Yuan, J., Wong, P., Ho, T.S., et al. (2015). Cancer immunology. Muta-
tional landscape determines sensitivity to PD-1 blockade in non-small cell lung
cancer. Science 348, 124–128.
Robbins, P.F., Lu, Y.C., El-Gamil, M., Li, Y.F., Gross, C., Gartner, J., Lin, J.C.,
Teer, J.K., Cliften, P., Tycksen, E., et al. (2013). Mining exomic sequencing
data to identify mutated antigens recognized by adoptively transferred tu-
mor-reactive T cells. Nat. Med. 19, 747–752.
Robinson, D.R., Wu, Y.M., Lonigro, R.J., Vats, P., Cobain, E., Everett, J., Cao,
X., Rabban, E., Kumar-Sinha, C., Raymond, V., et al. (2017). Integrative clinical
genomics of metastatic cancer. Nature 548, 297–303.
Rooney, M.S., Shukla, S.A., Wu, C.J., Getz, G., and Hacohen, N. (2015).
Molecular and genetic properties of tumors associated with local immune
cytolytic activity. Cell 160, 48–61.
Rous, P. (1911). A Sarcoma of the Fowl Transmissible by an Agent Separable
from the Tumor Cells. J. Exp. Med. 13, 397–411.
Sagiv-Barfi, I., Kohrt, H.E., Czerwinski, D.K., Ng, P.P., Chang, B.Y., and Levy,
R. (2015). Therapeutic antitumor immunity by checkpoint blockade is
enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc. Natl. Acad.
Sci. USA 112, E966–E972.
Sarkar, S., Bristow, C.A., Dey, P., Rai, K., Perets, R., Ramirez-Cardenas, A.,
Malasi, S., Huang-Hobbs, E., Haemmerle, M., Wu, S.Y., et al. (2017).
PRKCI promotes immune suppression in ovarian cancer. Genes Dev. 31,
1109–1121.
Savas, P., Salgado, R., Denkert, C., Sotiriou, C., Darcy, P.K., Smyth, M.J., and
Loi, S. (2016). Clinical relevance of host immunity in breast cancer: from TILs to
the clinic. Nat. Rev. Clin. Oncol. 13, 228–241.
Schumacher, T.N., and Schreiber, R.D. (2015). Neoantigens in cancer immu-
notherapy. Science 348, 69–74.
Schuster, C., Berger, A., Hoelzl, M.A., Putz, E.M., Frenzel, A., Simma, O.,
Moritz, N., Hoelbl, A., Kovacic, B., Freissmuth, M., et al. (2011). The cooperat-
ing mutation or ‘‘second hit’’ determines the immunologic visibility toward
MYC-induced murine lymphomas. Blood 118, 4635–4645.
Schwitalla, S., Ziegler, P.K., Horst, D., Becker, V., Kerle, I., Begus-Nahrmann,
Y., Lechel, A., Rudolph, K.L., Langer, R., Slotta-Huspenina, J., et al. (2013).
Loss of p53 in enterocytes generates an inflammatory microenvironment
enabling invasion and lymph node metastasis of carcinogen-induced colo-
rectal tumors. Cancer Cell 23, 93–106.
Shchors, K., Shchors, E., Rostker, F., Lawlor, E.R., Brown-Swigart, L., and
Evan, G.I. (2006). The Myc-dependent angiogenic switch in tumors is medi-
ated by interleukin 1beta. Genes Dev. 20, 2527–2538.
Shen, Q., Cohen, B., Zheng, W., Rahbar, R., Martin, B., Murakami, K., Lamorte,
S., Thompson, P., Berman, H., Zúñiga-Pflu €cker, J.C., et al. (2017). Notch
Shapes the Innate Immunophenotype in Breast Cancer. Cancer Discov. 7,
1320–1335.
Shin, D.S., Zaretsky, J.M., Escuin-Ordinas, H., Garcia-Diaz, A., Hu-Lieskovan,
S., Kalbasi, A., Grasso, C.S., Hugo, W., Sandoval, S., Torrejon, D.Y., et al.
(2017). Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations.
Cancer Discov. 7, 188–201.
Sodir, N.M., Swigart, L.B., Karnezis, A.N., Hanahan, D., Evan, G.I., and Sou-
cek, L. (2011). Endogenous Myc maintains the tumor microenvironment.
Genes Dev. 25, 907–916.
Soucek, L., Lawlor, E.R., Soto, D., Shchors, K., Swigart, L.B., and Evan, G.I.
(2007). Mast cells are required for angiogenesis and macroscopic expansion
of Myc-induced pancreatic islet tumors. Nat. Med. 13, 1211–1218.
Sparmann, A., and Bar-Sagi, D. (2004). Ras-induced interleukin-8 expression
plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458.
Spranger, S., Bao, R., and Gajewski, T.F. (2015). Melanoma-intrinsic b-catenin
signalling prevents anti-tumour immunity. Nature 523, 231–235.
Spranger, S., Luke, J.J., Bao, R., Zha, Y., Hernandez, K.M., Li, Y., Gajewski,
A.P., Andrade, J., and Gajewski, T.F. (2016). Density of immunogenic antigens
does not explain the presence or absence of the T-cell-inflamed tumor micro-
environment in melanoma. Proc. Natl. Acad. Sci. USA 113, E7759–E7768.
Stanton, S.E., Adams, S., and Disis, M.L. (2016). Variation in the Incidence and
Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes:
A Systematic Review. JAMA Oncol. 2, 1354–1360.
Stehelin, D., Varmus, H.E., Bishop, J.M., and Vogt, P.K. (1976). DNA related to
the transforming gene(s) of avian sarcoma viruses is present in normal avian
DNA. Nature 260, 170–173.
Stewart, T.A., Pattengale, P.K., and Leder, P. (1984). Spontaneous mammary
adenocarcinomas in transgenic mice that carry and express MTV/myc fusion
genes. Cell 38, 627–637.
Stiff, A., Trikha, P., Wesolowski, R., Kendra, K., Hsu, V., Uppati, S., McMichael,
E., Duggan, M., Campbell, A., Keller, K., et al. (2016). Myeloid-Derived Sup-
pressor Cells Express Bruton’s Tyrosine Kinase and Can Be Depleted in Tu-
mor-Bearing Hosts by Ibrutinib Treatment. Cancer Res. 76, 2125–2136.
Stodden, G.R., Lindberg, M.E., King, M.L., Paquet, M., MacLean, J.A., Mann,
J.L., DeMayo, F.J., Lydon, J.P., and Hayashi, K. (2015). Loss of Cdh1 and
Trp53 in the uterus induces chronic inflammation with modification of tumor
microenvironment. Oncogene 34, 2471–2482.
Topper, M.J., Vaz, M., Chiappinelli, K.B., DeStefano Shields, C.E., Niknafs, N.,
Yen, R.C., Wenzel, A., Hicks, J., Ballew, M., Stone, M., et al. (2017). Epigenetic
Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung
Cancer. Cell 171, 1284–1300 e1221.
Immunity 48, March 20, 2018 415

Toso, A., Revandkar, A., Di Mitri, D., Guccini, I., Proietti, M., Sarti, M., Pinton,
S., Zhang, J., Kalathur, M., Civenni, G., et al. (2014). Enhancing chemotherapy
efficacy in Pten-deficient prostate tumors by activating the senescence-asso-
ciated antitumor immunity. Cell Rep. 9, 75–89.
Van Allen, E.M., Miao, D., Schilling, B., Shukla, S.A., Blank, C., Zimmer, L.,
Sucker, A., Hillen, U., Foppen, M.H.G., Goldinger, S.M., et al. (2015). Genomic
correlates of response to CTLA-4 blockade in metastatic melanoma. Science
350, 207–211.
van Rooij, N., van Buuren, M.M., Philips, D., Velds, A., Toebes, M., Heemskerk,
B., van Dijk, L.J., Behjati, S., Hilkmann, H., El Atmioui, D., et al. (2013). Tumor
exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-
responsive melanoma. J. Clin. Oncol. 31, e439–e442.
Vanden Borre, P., Gunda, V., McFadden, D.G., Sadow, P.M., Varmeh, S., Ber-
nasconi, M., and Parangi, S. (2014). Combined BRAF(V600E)- and SRC-inhibi-
tion induces apoptosis, evokes an immune response and reduces tumor
growth in an immunocompetent orthotopic mouse model of anaplastic thyroid
cancer. Oncotarget 5, 3996–4010.
Ventura, A., Kirsch, D.G., McLaughlin, M.E., Tuveson, D.A., Grimm, J., Lintault,
L., Newman, J., Reczek, E.E., Weissleder, R., and Jacks, T. (2007). Restoration
of p53 function leads to tumour regression in vivo. Nature 445, 661–665.
von Hansemann, D. (1890). Ueber asymmetrische Zelltheilung in Epithelkreb-
sen und deren biologische Bedeutung. Virchows Arch. Path. Anat 119,
299–326.
Wang, G., Lu, X., Dey, P., Deng, P., Wu, C.C., Jiang, S., Fang, Z., Zhao, K., Ko-
naparthi, R., Hua, S., et al. (2016). Targeting YAP-Dependent MDSC Infiltration
Impairs Tumor Progression. Cancer Discov. 6, 80–95.
Wang, Q., Hu, B., Hu, X., Kim, H., Squatrito, M., Scarpace, L., deCarvalho,
A.C., Lyu, S., Li, P., Li, Y., et al. (2017). Tumor Evolution of Glioma-Intrinsic
Gene Expression Subtypes Associates with Immunological Changes in the
Microenvironment. Cancer Cell 32, 42–56 e46.
Welte, T., Kim, I.S., Tian, L., Gao, X., Wang, H., Li, J., Holdman, X.B., Hersch-
kowitz, J.I., Pond, A., Xie, G., et al. (2016). Oncogenic mTOR signalling recruits
416 Immunity 48, March 20, 2018
Immunity
Review
myeloid-derived suppressor cells to promote tumour initiation. Nat. Cell Biol.
18, 632–644.
Wislez, M., Fujimoto, N., Izzo, J.G., Hanna, A.E., Cody, D.D., Langley, R.R.,
Tang, H., Burdick, M.D., Sato, M., Minna, J.D., et al. (2006). High expression
of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia
induced by oncogenic kras. Cancer Res. 66, 4198–4207.
Wölfel, T., Hauer, M., Schneider, J., Serrano, M., Wölfel, C., Klehmann-Hieb,
E., De Plaen, E., Hankeln, T., Meyer zum Bu €schenfelde, K.H., and Beach, D.
(1995). A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lympho-
cytes in a human melanoma. Science 269, 1281–1284.
Wörmann, S.M., Song, L., Ai, J., Diakopoulos, K.N., Kurkowski, M.U.,
€ lu
Görgu €, K., Ruess, D., Campbell, A., Doglioni, C., Jodrell, D., et al.
(2016). Loss of P53 Function Activates JAK2-STAT3 Signaling to Promote
Pancreatic Tumor Growth, Stroma Modification, and Gemcitabine Resis-
tance in Mice and Is Associated With Patient Survival. Gastroenterology
151, 180–193.e12.
Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky,
V., Cordon-Cardo, C., and Lowe, S.W. (2007). Senescence and tumour clear-
ance is triggered by p53 restoration in murine liver carcinomas. Nature 445,
656–660.
Yang, Y. (2015). Cancer immunotherapy: harnessing the immune system to
battle cancer. J. Clin. Invest. 125, 3335–3337.
Yetil, A., Anchang, B., Gouw, A.M., Adam, S.J., Zabuawala, T., Parameswaran,
R., van Riggelen, J., Plevritis, S., and Felsher, D.W. (2015). p19ARF is a critical
mediator of both cellular senescence and an innate immune response associ-
ated with MYC inactivation in mouse model of acute leukemia. Oncotarget 6,
3563–3577.
Ying, H., Elpek, K.G., Vinjamoori, A., Zimmerman, S.M., Chu, G.C., Yan, H.,
Fletcher-Sananikone, E., Zhang, H., Liu, Y., Wang, W., et al. (2011). PTEN is
a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates
an NF-kB-cytokine network. Cancer Discov. 1, 158–169.